Neuroscience Research 86 (2014) 37–49

Contents lists available at ScienceDirect

Neuroscience Research

jo urnal homepage: www.elsevier.com/locate/neures

Review article

Neuronal subtype speciﬁcation in establishing mammalian

neocortical circuits

a a,b,∗

Takuma Kumamoto , Carina Hanashima

Laboratory for Neocortical Development, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan

Department of Biology, Graduate School of Science, Kobe University, Kobe 657-8501, Japan

a r a

t b

i c s t

l e i n f o r a c t

Article history: The functional integrity of the neocortical circuit relies on the precise production of diverse neuron popu-

Received 10 March 2014

lations and their assembly during development. In recent years, extensive progress has been made in the

Received in revised form 21 June 2014

understanding of the mechanisms that control differentiation of each neuronal type within the neocortex.

Accepted 23 June 2014

In this review, we address how the elaborate neocortical cytoarchitecture is established from a simple

Available online 11 July 2014

neuroepithelium based on recent studies examining the spatiotemporal mechanisms of neuronal subtype

speciﬁcation. We further discuss the critical events that underlie the conversion of the stem amniotes

Keywords:

cerebrum to a mammalian-type neocortex, and extend these key ﬁndings in the light of mammalian

Neocortex

evolution to understand how the neocortex in humans evolved from common ancestral mammals.

Cell fate speciﬁcation

Projection neuron BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). Layer Evolution

Contents

1. Introduction ...... 37

2. The classiﬁcation of neocortical glutamatergic neurons ...... 38

3. Spatial origins of neocortical glutamatergic neurons ...... 39

4. Temporal speciﬁcation of neocortical glutamatergic subtypes ...... 42

4.1. Cell competence and lineage of neocortical subtypes – a question revisited ...... 42

4.2. Genetic network underlying neocortical subtype segregation ...... 43

5. The mammalian-speciﬁc regulation of neocortical subtype speciﬁcation ...... 44

6. The evolvability of the neocortex – future perspectives ...... 45

7. Conclusions ...... 46

Acknowledgements ...... 46

References ...... 46

compatible with increased size and number of functional areas dur-

1. Introduction

ing mammalian evolution (Rakic, 2009). Although its anatomical

character has been long appreciated, the mechanisms underly-

The neocortex is comprised of diverse arrays of neurons that

ing the speciﬁcation and assembly of each neuronal component

are organized into laminar and columnar subdivisions and is

of the neocortex remain largely elusive. Despite common stem

the processing center for complex behaviors, including percep-

amniote origin, non-mammalian lineages develop highly disparate

tions, voluntary movements and languages. This unique laminated

brain cytoarchitectures, such as a single-layered cortex in rep-

brain system is observed throughout extant monotremes to

tiles (Dugas-Ford et al., 2012; Nomura et al., 2013) and a nuclear

humans (Haug, 1987; Meynert, 1868) and has proved to be highly

organization in birds (Jarvis et al., 2013; Montiel and Molnar,

2013; Nomura et al., 2008; Suzuki et al., 2012). The acquisi-

∗ tion of the laminated brain system is, therefore, one of the key

Corresponding author at: Laboratory for Neocortical Development, RIKEN Center

events that enabled unique neural processing in mammals and

for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-

may underlie high evolvability of the neocortex toward hominid

0047, Japan. Tel.: +81 78 306 3400; fax: +81 78 306 3401.

E-mail address: [email protected] (C. Hanashima). evolution.

http://dx.doi.org/10.1016/j.neures.2014.07.002

38 T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49

In recent years, approaches from both developmental and evolu- with dendrites of pyramidal neurons (Marin-Padilla, 1998; Meyer

tionary viewpoints have provided new insights into the molecular et al., 1999; Soriano and Del Rio, 2005; Villar-Cervino and Marin,

scenario underlying neocortical assembly and its function. The 2012) and express Reelin, p73 (Trp73) and/or calretinin, and CXCR4,

aim of this review is to decipher how the elaborate neocortical depending on their subtype of origin (De Bergeyck et al., 1998; Del

cytoarchitecture is uniquely established in mammals based on our Rio et al., 1995; Ogawa et al., 1995; Stumm et al., 2003). CR neurons

updated knowledge on the mechanisms of speciﬁcation of neuronal were originally identiﬁed by their unique morphology and distri-

subtypes. We then examine these homologous cell components bution within the marginal zone of developing human neocortex

in non-mammalian vertebrates to address the key events that (reviewed by Meyer et al., 1999). These neurons control the radial

underlie the conversion of the cerebrum of stem amniotes to a migration of projection neurons through their secretion of protein

mammalian-type neocortex. Finally, we extend these ﬁndings in Reelin. However, recent reports also indicate their roles in prolifera-

the light of mammalian evolution, to address how the neocortex in tion and areal patterning of later-born projection neurons (Griveau

humans may have evolved from ancestral mammals. et al., 2010; Teissier et al., 2012).

Neurons of layers II/III have distinct features from layer IV

neurons, although both are categorized into upper-layer (UL)

2. The classiﬁcation of neocortical glutamatergic neurons

projection neurons. Layers II/III pyramidal neurons establish

Neocortical neurons can be classiﬁed into subtypes accord- interhemispheric synaptic connections and mediate higher order

ing to their connectivity, morphology, physiology and molecular information processing through the integration of bilateral corti-

properties. Of these, two major classes based on neurotransmit- cal information. These neurons send axons to distant ipsilateral

ter expressions, glutamatergic projection neurons (approximately and contralateral neocortical areas: the latter of which are called

80%) and GABA (␥-aminobutyric acid)-ergic interneurons (approx- callosal projection neurons (CPN) and connect the two cerebral

imately 20%) create the sensory representation of the physical hemispheres by extending axons through the corpus callosum

world. While interneurons connect in the vicinity to provide inhibi- (Fame et al., 2011). These neurons have relatively small, pyramidal-

tion to the local circuit, projection neurons are excitatory and send shaped somata and conﬁned dendritic trees, and they form axonal

axons to distant cortical and subcortical targets (Bartolini et al., collaterals with neighboring cortical regions (Gilbert and Wiesel,

2013; Greig et al., 2013). Although these two populations inter- 1979; Lund et al., 1979). During the early postnatal period, most

mix within the mature neocortex, they are generated from different layers II/III projection neurons express the transcription factors

sectors of the telencephalon. Interneurons are produced from the Cux1/2, Brn1/2, Satb2 and the non-transcription factors Inhba and

ventral eminences (Anderson et al., 1997), whereas projection neu- Limch1 (Britanova et al., 2008; Franco et al., 2012; McEvilly et al.,

rons arise locally from the progenitors of the dorsal telencephalon 2002; Molyneaux et al., 2009; Nieto et al., 2004). In rodents, the

(Gorski et al., 2002). distinction between layers II and III is not as clear as in primates.

In principle, the cytoarchitecture of the neocortex can be deﬁned However, a few genes, including Frmd4b, Nnmt, Chn2 and Lpl, are

by its glutamatergic cell components. These excitatory neurons, expressed in a restricted subset of layers II/III neurons during mouse

which are arranged into horizontal layers, undergo further mod- development (Molyneaux et al., 2009). Importantly, lineage anal-

iﬁcations that assemble them into tangentially organized columns ysis using Cre recombinase expressed from the Cux2 gene locus

Cre/+

and areas (Noctor et al., 2001; Rakic, 1988). Each column, typically (Cux2 mice) has shown that Cux2-expressing cells predomi-

responding to a speciﬁc sensory stimulus, such as a body part or nantly contribute to layers II–IV neurons, which deﬁnes Cux2 as

sound representation, is considered a functional unit within the an UL neuron lineage marker (Franco et al., 2012).

respective neocortical area. After Meynert (1868), Lewis (1878) Neurons of layer IV, in turn, convey sensory information into

and Hammarberg (1895), Brodmann was the ﬁrst to unify the the neocortex by receiving input from peripheral organs. These

names of neocortical subtypes according to their laminar pos- neurons function as high-ﬁdelity gateway for sensory inputs, main-

itions and morphologies. Ever since, layers I through VI are still taining strict topographic organization and information transfer

used as common terminology in identifying the glutamatergic sub- to a given neocortical area. The glutamatergic neurons of layer

types organized along the radial axis from superﬁcial to deep. It is IV exhibit a variable dendritic pattern compared to other layers

important to recognize that although laminar positions are indica- (Staiger et al., 2004). For example, in the somatosensory cortex,

tive of their neuronal identity, the advent of molecular technology spiny stellate cells represent a distinctive class of glutamater-

has brought forth its limitation in deﬁning a speciﬁc subtype. gic neurons. These neurons differ in their morphology from the

For example, retrograde neuronal tracers combined with microar- more abundant pyramidal neurons by the lack of a polarized api-

ray analyses reveal further heterogeneity in cell populations even cal dendrite and conﬁne their dendritic arbor in the same layer,

within the same layer (Arlotta et al., 2005; Molyneaux et al., while typically projecting axons to layers II/III within the column

2009). Recent high-throughput transcriptome-proﬁling in rodents (Anderson et al., 1994; Martin and Whitteridge, 1984; Yoshimura

and primates has highlighted not only diverse expression pat- et al., 2005). In contrast to other layer neurons, the number of layer

terns of protein-coding genes but also noncoding RNAs within and IV neuron speciﬁc markers is limited of which Rorb, Unc5d and

across neocortical layers (Belgard et al., 2011; Bernard et al., 2012; Kcnh5 (or Eag2) have been identiﬁed so far (Ludwig et al., 2000;

Fertuzinhos et al., 2014). Therefore, a given neuronal type can only Saganich et al., 1999; Schaeren-Wiemers et al., 1997; Zhong et al.,

be deﬁned by supplemental criteria, including their molecular and 2004).

hodological properties. Based on these, the classiﬁcation of rep- Neurons of layer V, together with layer VI neurons, are grouped as

resentative layer glutamatergic neurons currently falls into the deep-layer (DL) neurons and consist mainly of corticofugal projec-

following subtypes, which has been best delineated in mice. tion neurons. Layer V neurons project to the brainstem and spinal

Layer I is a relatively cell sparse layer, which accommodates cord, and express Fezf2 and Ctip2, and a subset of these express

mainly intercellular synapses of axonal ﬁbers and dendritic tufts of ER81 (Chen et al., 2005a,b; Inoue et al., 2004; Molnar and Cheung,

pyramidal neurons. However, it consists of a unique neuron popu- 2006; Molyneaux et al., 2005; Yoneshima et al., 2006). Although

lation called Cajal–Retzius (CR) cells during development. Although layer V neurons are mostly subcerebral projection neurons (SCPNs),

approximately 75% of CR cells present at birth die before the sec- it is notable that approximately 20% of neocortical CPNs localize in

ond postnatal week in mice (Del Rio et al., 1995; Soda et al., 2003), layer V, and these neurons are similar to layers II/III CPNs in their

some CR cells survive to adulthood (Chowdhury et al., 2010). CR molecular expression and connectivity (Molyneaux et al., 2009).

cells extend long horizontal axons and form synaptic contacts Notably, layer V contains large pyramidal neurons that are disposed

T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49 39

in radial clusters; these neurons express speciﬁc subsets of genes et al., 2003) (Fig. 1B). The boundary between the pallium and sub-

such as Ctip2 and Id2, and are segregated from CPNs that occupy pallium (pallial–subpallial boundary; PSB) is established through

the same layer (Kwan et al., 2012; Maruoka et al., 2011). These cross-repression between Gli3 and Shh, and Fgf8 expression (Gutin

observations imply that projection neurons of common molecular et al., 2006; Rallu et al., 2002). Through these interactions, the bor-

+ +

proﬁles are further organized into microdomains within the same der between the Pax6 pallium and the Nkx2.1 subpallium is ﬁrst

layer. In turn, layer VI neurons establish corticothalamic projection established around E9.5 (Shimamura et al., 1995) (Fig. 1B), which

neurons (CThPNs) and express Tbr1, Zfpm2, and Sox5 (Hevner et al., is subsequently replaced by a Pax6/Gsx2 boundary by E12.5 (Yun

2001; Kwan et al., 2008). Layer VI neurons exhibit greater variabil- et al., 2001).

ity in their dendritic patterns; however, the correspondence of their After this, the entire pallium is deﬁned by Pax6 expression in

morphology and gene expression is less deﬁned compared to other the progenitors and Tbr1 expression in the postmitotic neurons

layers. (Puelles et al., 2000), although Tbr1 is downregulated in many of the

Subplate neurons (alternatively called layer VIb or layer VII neu- layers II–V neurons (Han et al., 2011). Notably, although the expres-

rons), are also early-generated neurons in the neocortex that have sion of Emx2 and Pax6 extends into the dorsal pallial territory, the

undergone expansion during mammalian evolution (Montiel et al., enhancer that drives expression in the caudal forebrain and dorsal

2011; Smart et al., 2002). Subplate cells are identiﬁed by their deep- pallium appears to be different (Kammandel et al., 1999; Kleinjan

est position in the cortical plate and expression of CTGF, Cplx3, et al., 2004; Theil et al., 2002). Emx1 is further restricted in its lateral

and Lpar1 during the perinatal periods (Hoerder-Suabedissen and extent (Fernandez et al., 1998), where it delineates an expression

Molnar, 2013); however, earlier, they share several molecular fea- boundary between the lateral and ventral pallium (Puelles et al.,

tures with layer VI neurons (Hevner et al., 2001; Kwan et al., 2008; 2000) (Fig. 3C, left panel). The medial pallium, in turn, is deﬁned

Lai et al., 2008). Subplate neurons serve as initial scaffolds for thala- by the expression of multiple Wnts (Wnt3a, Wnt5a and Wnt2b)

mic afferents into the neocortex and provide the earliest excitatory by E9.5 (Parr et al., 1993) (Fig. 1A and B). Currently, the molecular

inputs into the neocortex (Ghosh et al., 1990; Kanold et al., 2003). boundary that delineates the lateral and dorsal pallium progeni-

While subplate neurons are also considered to be largely transient tors is not clear; it is suggested that Cadherin 8 is expressed higher

cells in mice (Price et al., 1997), a proportion of these cells remain in the lateral pallium than that of the dorsal pallium derivatives

in postnatal primate cortices (Judasˇ et al., 2010; Kostovic and Rakic, (Medina et al., 2004).

1980). Thus, subplate cells may also function beyond early circuit Based on gene expression and genetic fate-mapping studies, it is

formation. clear that most neocortical glutamatergic neurons arise from pro-

genitor cells of the Emx1-positive Wnt3a-negative dorsal pallial

sector (Gorski et al., 2002; Louvi et al., 2007) (Fig. 3C, left). The

3. Spatial origins of neocortical glutamatergic neurons medial and lateral/ventral pallium, in turn, gives rise mainly to hip-

pocampus and olfactory cortex/amygdala neurons (Medina et al.,

The intricate cytoarchitecture of the neocortex has long 2004). There are two exceptions, however, where these sectors con-

attracted neuroscientists to investigate how the diversity of neu- tribute to neurons of the neocortex: these are the early-generated

rons are created and how their precise integration is coordinated neurons, CR cells and Dbx1-expressing transient glutamatergic

during development. For this, it is worthwhile to consider the neurons (Garcia-Moreno et al., 2007; Teissier et al., 2010, 2012).

mechanisms by which neocortical subtypes are generated along After a long assumption that CR cells are generated from the dorsal

both the spatial and temporal axis. Despite its complexity, the neo- pallium, Meyer was the earliest to suggest that Reelin-expressing

cortex starts as a simple sheet of neuroepithelium at the anterior CR cells arise from a discrete pallial sector in the neuroepithe-

end of the neural plate of which the dorsal sector of the tele- lium and enter the neocortex by tangential migration (Meyer et al.,

ncephalon becomes the pallium. The pallium is divided into four 1999). Later, p73 was identiﬁed as an alternative CR cell marker

proliferative zones according to molecularly deﬁnable boundaries: and demonstrated a similar tangential spread from the medial and

medial, dorsal, lateral and ventral pallium (Fig. 1A). Here, we focus ventral pallium to the dorsal pallium (Meyer et al., 2002).

exclusively on the establishment of these subdivisions in three- The experimental evidence for non-dorsal pallium-derived

dimensions to address the neocortical subtypes that arise from each CR cells ﬁrst came from exo utero electroporation of LacZ-

sector. expressing plasmids, where cells labeled in the medial pallium

Extensive studies in mice have shown that early forebrain pat- with LacZ spread tangentially into the surface of the dorsal pallium

terning is established between 3 and 6 somite stages (∼embryonic (Takiguchi-Hayashi et al., 2004). Later, genetic fate-mapping using

Cre/+ Cre/+

day (E)8.0) through the reciprocal action of transcription factors Wnt3a mice (Yoshida et al., 2006) and Dbx1 mice (Bielle

and morphogens. The anterior neuraxis is instructed through the et al., 2005) revealed the medial and ventral pallium as source of

head organizer activity of the anterior visceral endoderm. Subse- CR cells. It is important to clarify here that (1) the medial pallium

quently, Otx2 (induced by the anterior neuroectoderm enhancer, contains the region of cortical hem and choroid plexus and (2) the

Fig. 1A and B) establishes the forebrain and midbrain territories ventral pallium connects caudally to the thalamic eminence and

through an antagonistic effect on Gbx2 (∼6-somite stage) (Inoue rostrally to the septum (Kimura et al., 2005; Puelles, 2011; Roy et al.,

et al., 2012; Kurokawa et al., 2004, 2014; Millet et al., 1999). Within 2013). Although these regions (cortical hem, choroid plexus, thala-

the forebrain, the expression of Emx2 (3-somites∼) (Simeone et al., mic eminence) have been considered as independent sources of CR

1992; Suda et al., 2001) and Pax6 (late 4-somites∼) (Inoue et al., cells (Imayoshi et al., 2008; Tissir et al., 2009; Yoshida et al., 2006),

2000) functions redundantly to establish the caudal forebrain, they correspond to the derivatives of the caudal forebrain, which

which contributes to the medial and ventral pallium (shown in are initially established by Emx2 and Pax6 (Kimura et al., 2005)

green and light blue in Fig. 1A and B) and diencephalon (Kimura (Fig. 1B).

et al., 2005). In parallel, rostrally, Six3 is expressed at the anterior Two transcription factors, Foxg1 and Lhx2, in turn, establish the

neural plate after E8.2 (Oliver et al., 1995) (Fig. 1B) and represses dorsal pallium progenitors. Foxg1, a forkhead-box family protein,

Wnt1 to establish the rostral forebrain domain (Lagutin et al., marks the anterior forebrain from early vertebrates (Bardet et al.,

2003). The expression of Fgf8 in the anterior neural ridge (ANR) 2010; Toresson et al., 1998). Consistent with its expression, Foxg1

commences at approximately 4-somites (Suda et al., 1997), which has an evolutionary conserved role in vertebrate telencephalic

induces Foxg1 in the Six3-expressing domain and establishes the development; in Xenopus, zebraﬁsh, chickens and mice, Foxg1 reg-

dorsal pallium and subpallium (Kobayashi et al., 2002; Lagutin ulates telencephalic growth (Ahlgren et al., 2003; Hanashima et al.,

40 T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49

Fig. 1. The genetics of early pallial patterning. (A) Spatiotemporal gene expressions in the developing forebrain before (E8.5) and after (E9.5∼) neural tube closure. Left and

right hemispheres show the expression pattern of a different set of genes; same expression pattern applies to the contralateral hemisphere. Coronal view indicates spatial

subdivisions of the pallium, where dorsal pallium lies between the medial and lateral/ventral pallium. In sagittal view, the medial and lateral/ventral pallium connects at

caudal levels. DP, dorsal pallium; LP, lateral pallium; me, mesencephalon; MP, medial pallium; pr, prosencephalon; SP, subpallium; VP, ventral pallium. (B) The early forebrain

patterning in mouse embryo is established between 3 and 6 somite stages (E8.0–E8.5) through the reciprocal action of transcription factors and morphogens. Otx2 (induced

by the anterior neuroectoderm (AN) enhancer) establishes the forebrain and midbrain. Emx2 (3-somites∼) and Pax6 (4-somites∼) functions redundantly to establish the

caudal forebrain, which contributes to the medial pallium, ventral pallium and diencephalon. Six3 is expressed at the anterior neural plate around E8.2 and establish the

rostral forebrain domain (red). The expression of Fgf8 in the anterior neural ridge (ANR) commences at approximately 4-somites, which induces Foxg1 in the Six3-expressing

domain and establishes the dorsal pallium and subpallium. The establishment of the subpallium further requires Shh and Nkx2.1. The PSB shown as a Pax6/Nkx2.1 boundary

is later replaced with a Pax6/Gsh2 boundary by E12.5.

T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49 41

Fig. 2. Spatiotemporal switch in early CR cells to projection neuron identity by Foxg 1. (A) Cell-autonomous induction of Ctip2 DL projection neurons by Foxg1. In utero

−/−

electroporation of pCAGGS-GFP and pCAGGS-Foxg1 into E14.5 Foxg1 cortex examined at E18.5. (B) Temporal competence for CR cell and DL neurogenesis in wildtype

−/−

and Foxg1 mutant mice. All scheme illustrates E18.5 cortex. From left to right: (a) wildtype, (b) constitutive Foxg1 knockout (Foxg1 ), (c) conditional removal of Foxg1

expression during the DL production period (at E13), (d) late induction of Foxg1 (at E14.5) (Foxg1 E9.5–14.5 OFF, E14.5–E18.5 ON), (e) in utero electroporation of Foxg1 into

−/− −/−

E14.5 Foxg1 cortex (E14.5 Foxg1 EP). Foxg1 results in prolonged CR cell production at the expense of DL and UL neurons. E13 conditional knockout of Foxg1 during the DL

production period results in the reversion of DL progenitors to generate CR cells. Conversely, E14.5 induction of Foxg1 is sufﬁcient to induce DL neurogenesis after prolonged

−/− + +

CR neurogenesis. In utero electroporation of Foxg1 into E14.5 Foxg1 cortex is sufﬁcient to induce Ctip2 and Fezf2 DL projection neurons, indicating cell-autonomous

requirement for Foxg1 in switching from CR cells to DL neurons (Kumamoto et al., 2013). (C) Model for the switch in neurogenesis in the cerebral cortex. Foxg1 (red) is

induced in the anterior neural ectoderm through rostral Fgf8 expression (yellow) and expands caudally in the neural plate. After neural tube closure, Foxg1 shifts the rostral

limit of caudal telencephalic gene expression (Ebf2/3, Zic3, Lhx9, Dmrt3, Eya2) within the neuroepithelium (indicated in green) and initiates projection neuron production in

the dorsal progenitors. Expression of these genes is only observed rostrally in migrating CR neurons. The cortical hem corresponds to the dorsal part of the CR cell competent

+ +

region (green) in the sagittal section. Ventrally, the caudal limits of Foxg1 expression are the PSB and thalamic eminence (Sfrp2 and Dbx1 region in Fig. 1A and B). cKO,

conditional knockout; CPe, choroid plexus; EP, electroporation; ThE, thalamic eminence.

42 T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49

2002; Regad et al., 2007) and patterning (Manuel et al., 2010; Roth appears to be secondary to the loss of ventral gene expression

et al., 2010) through antagonizing TGF-b/Smad pathways (Seoane (Fig. 1A and B). These observations are consistent with the primary

et al., 2004) and repressing p27Kip1 expression (Hardcastle and targets of Foxg1 and Lhx2 being largely non-redundant (Hou et al.,

Papalopulu, 2000). Studies in mice and chickens show that Foxg1 2013; Kumamoto et al., 2013; Tao and Lai, 1992).

is induced by Fgf8 within the Six3-expressing domain (Kobayashi

et al., 2002; Shimamura et al., 1995); however, an interesting regu-

4. Temporal speciﬁcation of neocortical glutamatergic

latory conservation is reported in hemichordates (Pani et al., 2012).

subtypes

Studies in zebraﬁsh reveal that Foxg1 establishes the dorsal pallium

and subpallium by repression of the Wnt8b promoter through its

4.1. Cell competence and lineage of neocortical subtypes – a

binding to a vertebrate-conserved sequence (Danesin et al., 2009).

question revisited

Notably, studies using conditional mutant mice identiﬁed multi-

ple Foxg1-repressed target genes expressed in both the medial and At the time each pallium domain is established, the neuro-

ventral pallium (Eya2, Dmrt3, Zic3, Ebfs), and some of these binding epithelial cells of the dorsal pallium give rise to radial glial cells

sites were speciﬁc to mammals (Kumamoto et al., 2013). Conse- (RGCs), which are more fate-restricted progenitors. The successive

quently, in the absence of Foxg1, the medial and ventral pallium replacement of neuroepithelial cells to RGCs may be instructed by

expands at the expense of the dorsal pallium (Danesin et al., 2009; several molecules (Kang et al., 2009; Sahara and O’Leary, 2009)

Kumamoto et al., 2013) (Fig. 2C). and terminates the competence of dorsal pallium progenitors to

Lhx2 is a LIM-homeodomain transcriptional factor, which is respond to the loss of Lhx2 (Chou et al., 2009) but still requires

expressed in a medial-high to lateral-low graded pattern across the Foxg1 (Hanashima et al., 2004). The earliest neurons in the neo-

dorsal pallium, and it delineates the boundary with the medial pal- cortex appear at the surface of the dorsal pallium around E10–E11

lium (Monuki et al., 2001) (Fig. 3C). Both Lhx2 constitutive knockout and are tangentially migrating CR cells generated from the medial

−/−

mice and chimera studies using Lhx2 <-> wildtype cells indi- and ventral pallium, which form the preplate. After CR cell produc-

cate that Lhx2 is required for dorsal pallium speciﬁcation, and its tion, most neocortical glutamatergic neurons arise from the RGCs

absence results in the expansion of both the medial and ventral of the dorsal pallium, which migrate radially toward the pia and

pallium at the expense of the dorsal pallium (Bulchand et al., 2001; position themselves beneath the CR cells. Neurons are generated

Mangale et al., 2008). Notably, the requirement for Lhx2 in the dor- successively and migrate past the pre-existing, early-born neurons

sal pallium has a restricted temporal window; whereas removal and allocate to the more superﬁcial layers in an “inside-out” dis-

of Lhx2 before E10.5 converts it to both a medial and lateral pal- tribution, a unique pattern observed in the mammalian neocortex

lium fate, conditional knockout between E10.5 and E11.5 results (Cooper, 2008; Hevner et al., 2003).

in expansion of the lateral and ventral pallium but not the medial Based on both in vitro and in vivo analysis, it has been suggested

pallium, and after E11.5, Lhx2 is no longer required to maintain the that the sequential generation of layer subtypes is regulated by an

dorsal pallium identity (Chou et al., 2009; Mangale et al., 2008). intrinsic program that switches progenitor cell competence over

Within the forebrain, the expression of Emx2 (3-somites∼) and time. In vivo clonal analysis demonstrated that a common pro-

Pax6 (4-somites∼) precedes that of Foxg1 and Lhx2, which com- genitor could contribute to neurons that encompass both deep

mences around 5-somites (E8.0) and E8.5, respectively (Mangale and upper cortical layers (Luskin et al., 1988; Price and Thurlow,

et al., 2008; Tao and Lai, 1992) (Fig. 1B). This implies that Foxg1 and 1988; Reid et al., 1995; Walsh and Cepko, 1988, 1992). In vitro, DL

Lhx2 specify the dorsal pallium after the medial and ventral pallium neurons were commonly generated after fewer cell divisions than

is established (Fig. 1B). Genetic fate-mapping and loss-of-function UL neurons, and progenitors from later-stage embryos were more

analysis further imply that these two (rostral and caudal) forebrain restricted in their ability to generate earlier-born neuronal sub-

territories are derived from a distinct lineage; the compound loss types in vitro (Shen et al., 2006) and in vivo (Frantz and McConnell,

of Emx2 and Pax6 results in the loss of the medial and ventral pal- 1996; McConnell, 1988; McConnell and Kaznowski, 1991). Corti-

lium but not the dorsal pallium or subpallium (Kimura et al., 2005). cal cells derived from mouse embryonic stem cells demonstrated

Notably, while Foxg1 and Lhx2 are both required to establish the that the temporal order by which stem cells generate neocortical

dorsal pallium, at caudal levels, Foxg1 delineates a sharp border glutamatergic subtypes could be replicated in vitro (Eiraku et al.,

at the ventral pallium and exhibits a gradient at the medial pal- 2008; Gaspard et al., 2008). These studies implied that the deﬁned

lium; Lhx2 shows the opposite trend with a sharp boundary at the temporal order of projection neuron subtypes in the neocortex is

medial pallium and a graded expression at the lateral/ventral pal- controlled by intrinsic changes in progenitor cell competence over

lium (Kumamoto et al., 2013; Monuki et al., 2001; Allen Brain Atlas, time.

http://www.brain-map.org). In this regard, recently, two alternative perspectives concern-

Currently, evidence for genetic interactions between Lhx2 and ing the lineage of neocortical neurons have been proposed. Cux2,

Foxg1 is lacking: knockout and chimera studies have shown that which is expressed in layers II–IV neurons in the mature neocortex,

−/−

within the cortex Foxg1 cells express Lhx2 caudally, whereas is expressed at a low level in RGCs at early embryonic stages. Using

−/− CreER/+

Lhx2 progenitors retain Foxg1 expression laterally (Mangale an inducible Cre recombinase knocked into Cux2 locus (Cux2 ),

et al., 2008; Muzio and Mallamaci, 2005). This implies that Foxg1 a subset of RGCs was labeled by the recombination of a reporter

and Lhx2 function cooperatively but independently to establish with tamoxifen administration at E10.5; however, these progeni-

the dorsal pallium identity. This is consistent with their distinct tors mainly contributed to UL neurons (Franco et al., 2012). These

temporal requirements for cortical speciﬁcation. The removal of results implied that a subpopulation of early cortical progenitors

Foxg1 at E13 is sufﬁcient to convert the dorsal pallium to a medial are dedicated to produce UL neurons but are restricted in their

and ventral pallium identity (Hanashima et al., 2007; Kumamoto differentiation until the appropriate timing at a later corticogen-

et al., 2013), but the conditional removal of Lhx2 exhibits an esis period. This view is somewhat different from a lineage study

early (approximately E11.5) competence window for a dorsal to using a Fezf2 BAC-transgenic Cre mouse line, which revealed that

lateral/ventral pallium conversion (Chou et al., 2009). Another dif- Fezf2-expressing progenitors can mark DL–UL-glia clones during

ference between Foxg1 and Lhx2 is that while Lhx2 is dispensable the early corticogenesis phase and UL-glia clones at late corticogen-

for subpallium development (Bulchand et al., 2001), Foxg1 is essen- esis phase (Guo et al., 2013). Although a simplistic interpretation of

tial for ventral telencephalic identity (Martynoga et al., 2005). Thus, these results is that neocortical progenitors comprise both lineage-

−/−

the absence of obvious ventral pallium expansion in Foxg1 cells restricted and progressively restricted clones, the entire picture

T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49 43

Fig. 3. Comparison of homologous subtypes and progenitor domains across amniotes. (A) Whole brain view of neonatal (P0) Chinese softshell turtle (Pelodiscus sinensis;

reptiles), chick (Gallus gallus; birds) and mouse (Mus musculus; mammals). (B) Cross-species homology between the pallial neuron subtypes based on gene expression and

connectivity. In the turtle, the rostral cortical area D2 corresponds to input sensory zones of the anterior DVR and expresses Rorb. The layer V marker ER81 labels the

intermediate and posterior ﬁelds of area D2. In birds, thalamorecipient neurons allocate to the entopallium and Field L, both of which express Rorb, a representative marker

for neocortical layer IV neurons. In turn, neocortical layer V marker ER81 is expressed in the chicken arcopallium and HA in the hyperpallium. (C) Dorsoventral patterning

of the telencephalon and respective pallial domains in mouse and chick embryos. Data are from mouse (E9.5–12.5) and chick (E4–E8) expression studies of mouse: Emx1/2,

Pax6, Ngn2, Dlx2, Sommer et al. (1996), Puelles et al. (2000), Yun et al. (2001), Muzio et al. (2002), Backman et al. (2005); Wnt3a, Wnt8b, Bmp4, Foxg1, Parr et al. (1993),

Hanashima et al. (2007); Lhx2, Monuki et al. (2001), Chou et al. (2009), Mangale et al. (2008); Dbx1, Medina et al. (2004), Bielle et al. (2005); Sfrp2, Kim et al. (2001), and

chick: Emx1/2, Lhx2, Pax6, Dlx2, von Frowein et al. (2006), Puelles et al. (2000); Foxg1, Bell et al. (2001); Ngn2, Sfrp1, von Frowein et al. (2002); Wnt8b, Garda et al., 2002.

In mouse, the expression of Emx1, Emx2 and Ngn2 extends into the Wnt3a medial pallium domain. Emx1 is expressed in both progenitors and post-mitotic neurons in the

dorsal and lateral pallium, but its expression is restricted to post-mitotic neurons in the ventral pallium. Rostrally, Foxg1 expression extends to the subpallium; at caudal

levels, Foxg1 expression is absent in the ventral pallium (Kumamoto et al., 2013). While it has been suggested that Lhx2 expression is restricted to the pallium at E12.5

(Monuki et al., 2001), at E11.5, Lhx2 expression extends into the subpallium (Chou et al., 2009). A, arcopallium; B, basorostralils; D2, ﬁeld D2; DC, dorsal cortex; DVR, dorsal

ventricular ridge; E, entopallium; Hi, hippocampus; Hy, hyperpallium; L2, ﬁeld L2; LC, lateral cortex; M, mesopallium; MC, medial cortex; N, nidopallium; NC, neocortex; OC,

olfactory cortex; Str, striatum, Th, thalamus.

of neocortical cell lineage and its neurogenesis timing regulation layer subtypes of the cerebral cortex are established with a closed

requires an unbiased and comprehensive clonal analysis to assess transcriptional network (Alcamo et al., 2008; Bedogni et al., 2010;

the relative contribution of each lineage in the mature neocortex. Britanova et al., 2008; Chen et al., 2008; Han et al., 2011; McKenna

Such experiments will also provide insights into the mechanisms et al., 2011; Srinivasan et al., 2012). Within these, repressor

that underlie the precise connectivity between clonally related networks are the major regulatory cascades responsible for seg-

sister DL and UL projection neurons (Yu et al., 2009, 2012). regating subtype identities. Tbr1, Fezf2 and Satb2 are expressed in

CThPNs, SCPNs and CPNs, respectively, where the loss of any one

of these genes results in a switch to alternative subtype identities

4.2. Genetic network underlying neocortical subtype segregation

(Alcamo et al., 2008; Chen et al., 2008; Han et al., 2011; McKenna

−/− +

Despite the ambiguity of their lineage relationships, molecular et al., 2011). For example, in Fezf2 knockout mice, Satb2 CPNs

mechanisms that segregate layer neuron subtype identities have and Tbr1 CThPNs appear at the expense of SCPNs (Bedogni et al.,

been made clearer. Genetic studies have shown that the principal 2010; Chen et al., 2005a; McKenna et al., 2011; Molyneaux et al.,

44 T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49

2005), while forced expression of Fezf2 is sufﬁcient to reprogram the latter to layer V projection neurons in mammals. In avians,

layers II/III CPNs and layer IV neurons to layer V/VI corticofugal visual information from the optic tectum is relayed by the nucleus

neuron identity (Chen et al., 2005b; De la Rossa et al., 2013; Rouaux rotundus of the thalamus and enters the entopallium, and auditory

−/−

and Arlotta, 2013). In Tbr1 mice, DL neurons upregulate Fezf2 information is relayed through the thalamic auditory nucleus to

expression and project inappropriately to the pons (Han et al., 2011; neurons in Field L (Fig. 3B). These thalamorecipient neurons express

−/− +

McKenna et al., 2011). In Satb2 mice, Ctip2 SCPNs increase Rorb, a representative marker for neocortical layer IV neurons. In

(Britanova et al., 2008). Of these transcription factors, only Fezf2 turn, at least three of the neocortical layer V markers, Er81, Fezf2

is expressed in both progenitors and post-mitotic neurons (Hirata and Pcp4, are expressed in the chicken arcopallium in the avian

et al., 2004), whereas others are only detectable in post-mitotic dorsal ventricular ridge (DVR; a characteristic protrusion into the

cells (Alcamo et al., 2008; Arlotta et al., 2005; Britanova et al., 2008; lateral ventricle in sauropsids) and hyperpallium (Fig. 3B). In the

Hevner et al., 2001). Furthermore, the segregation of these mark- turtle, the rostral area D2 corresponds to input sensory zones of

ers is only evident in postmitotic neurons: E13.5-born DL neurons the anterior DVR and expresses Rorb and Eag2 (Dugas-Ford et al.,

initially co-express Satb2 and Ctip2, but later they are segregated 2012; Ulinski, 1986) (Fig. 3B). By contrast, the layer V marker ER81

into CPN and SCPN subtypes (Alcamo et al., 2008; Srinivasan et al., labels the intermediate and posterior ﬁelds of area D2, which are

2012). Sox5, Fezf2 and Ctip2 are also coexpressed in many young expressed complementary with Rorb at a single cell resolution

corticofugal neurons of layers V/VI and SP. However, as corticogen- (Dugas-Ford et al., 2012) (Fig. 3B). Satb2- and Ctip2-expressing neu-

esis proceeds, Sox5 expression in post-mitotic cells represses Fezf2 rons also comprise largely complementary populations in the gecko

expression in layer VI neurons (Kwan et al., 2008; Lai et al., 2008; pallium (Nomura et al., 2013), although the projection targets of

Srinivasan et al., 2012). Therefore, it appears that some of these these neurons are still unclear. These observations imply that in

commitments take place at postmitotic levels. However, since the sauropsids, the homologous subtypes may allocate across multiple

expression of many transcription factors is downregulated during pallial sectors and are not solely dorsal pallium derivatives.

migration, the extent of cell fate decisions controlled at progenitor The correspondence of a few genes may be insufﬁcient to claim

levels is not clear. homology between mammals and sauropsid pallial neuron sub-

In this regard, Foxg1 plays a key role in early fate transition types. In this regard, recently, a comprehensive transcriptome

within progenitors. Conditional removal of Foxg1 in DL progeni- analysis has been performed by two groups (Belgard et al., 2013;

tors switches these progenitors to adopt a CR cell fate; however, its Chen et al., 2013; Jarvis et al., 2013). Based on the expression anal-

removal in postmitotic neurons does not revert DL neurons into yses of 52 genes in the zebra ﬁnch, (Jarvis et al., 2013) proposed

CR cells (Kumamoto et al., 2013). In turn, delayed induction of a new compartment model in avians based on gene expression

Foxg1 at E14.5 in vivo reveals that CR progenitor cells can generate similarities between subdomains of the bird pallium and mam-

+ +

Ctip2 /Fezf2 DL neurons at a progressively later stage of neocor- malian neocortex. Comparative transcriptomics of over 5000 genes

ticogenesis (Kumamoto et al., 2013) (Fig. 2A and B). Genome-wide in the adult chick and mouse cerebrum also revealed some con-

analysis reveals that the onset of Foxg1 expression represses mul- vergence between the different sectors of these species, but also

tiple transcriptional factors (Dmrt3, Eya2, Ebf2/3, and Zic3) that highlighted divergent molecular characters (Belgard et al., 2013;

are expressed in the progenitors of CR cells (Fig. 2C). These results Montiel and Molnar, 2013). Interestingly, in vitro clonal analysis in

indicate that although the initial medial/ventral and dorsal pallium the chick implies conservation between the temporal neurogenesis

territories are established independently, the progenitor cells that programs of mice and chicks (Suzuki et al., 2012). In these experi-

generate CR neurons and DL neurons are interconvertible; their ments, chick pallial progenitors produce layer speciﬁc subtypes in

competence switch is strictly regulated by a single transcription a similar chronological sequence in vitro as those observed in mam-

factor, Foxg1 (Fig. 2A and B). Taken together, the speciﬁcation of mals (Suzuki et al., 2012). Furthermore, recent birthdating studies

neocortical layer neurons involves the following two steps: (1) the in the gecko showed that the Satb2- and Ctip2-expressing cells in

suppression of a default CR cell identity and commitment to pro- the dorsal pallium also exhibited a similar trend in their tempo-

jection neuron fate through Foxg1-mediated gene cascade and (2) ral production, where many Ctip2 cells are generated earlier than

cross-regulatory determination of layer subtypes through subtype- Satb2 cells (Nomura et al., 2013). These results raise an intrigu-

speciﬁc transcription factors (Fig. 2C). ing possibility that the temporal program of the neurogenesis of

projection neuron subtypes emerged early in stem amniotes.

Given that the gene expression, axonal connections, and even

5. The mammalian-speciﬁc regulation of neocortical the temporal programs of neuronal subtypes are conserved, the

subtype specification mechanisms that underlie the changes in the final configuration

of neuronal subtype allocation within each vertebrate class appear

To what extent is the developmental program that directs pat- to rely on other elements. For this, at least two changes between

terns of neurogenesis and their assembly ‘neocortex’ speciﬁc? To mammals and sauropsids can be argued. One possibility is that each

discuss this, it is necessary to deﬁne the homologous subtypes of pallial sector may undergo disproportional expansion in saurop-

neocortical neurons and their progenitors across amniotes. Because sids, thereby spatially modifying their neurogenesis program. It is

of the nature of evolution, such identiﬁcation must rely on multiple important to note that in general, the rostrocaudal and dorsoven-

criteria. Indeed, there is still a debate concerning the cross-species tral patterning of the telencephalon is conserved across amniotes,

homology between the pallial neuron subtypes. This is because, at and the expression of Pax6, Tbr1, and Emx1 and the emergence

a glance, the cytoarchitecture of the cerebrum is highly variable of the four pallial sectors are similar in both birds and reptilians

between amniotes; reptiles use a mono-layered cortex for their (Puelles et al., 2000) (Fig. 3C). An exception is that the chick ven-

information processing (Cheung et al., 2007; Nomura et al., 2013), tral pallium does not express Dbx1 as found in the mouse (Bielle

whereas birds undergo nucleotypic organization to form mature et al., 2005) (Fig. 3C). Instead, the Pax6 domain contacting the

cerebral circuits (Jarvis et al., 2013; Montiel and Molnar, 2013; subpallium expresses Sfrp1 (von Frowein et al., 2002), a homo-

Nomura et al., 2008). logue of Sfrp2, which is expressed in the mouse ventral pallium

Dugas-Ford et al. (2012) took particular interest in the gene (Assimacopoulos et al., 2003) (Fig. 3C). However, the subsequent

expression and connectivity between neurons of the neocortex and transformation of each pallial sector to mature cerebral struc-

sauropsid pallium. In particular, they focused on thalamorecipi- tures is quite distinct between mammals and sauropsids. While

ent neurons and SCPNs; the former corresponds to layer IV and the contribution of the medial pallium to the hippocampus and

T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49 45

parahippocampal area, the lateral pallium to the olfactory cortex, to the size expansion of the cortical hem and CR cell number in

and the ventral pallium to the pallial amygdalar nuclei is similar mammals.

(Abellan and Medina, 2009), the avian dorsal pallium consists of

the hyperpallium (also called the Wulst) and the ventral pallium 6. The evolvability of the neocortex – future perspectives

largely contributes to the DVR (Bell et al., 2001; Striedter et al.,

1998). The anterior DVR contains auditory, visual, and somatosen- As mentioned, CR cells may be one feature that characterizes the

sory recipient regions and the neurons of the posterior DVR projects mammalian neocortex within the amniote brains. Until recently,

to the ventromedial and lateral hypothalamus (Bruce and Neary, the identiﬁcation of CR cells has relied on the expression of Reelin,

1995a,b). Thus, neuronal components of similar properties with which is the only marker identiﬁed to be expressed in all CR cell sub-

respect to their input/output connections have undergone distinc- types in mammals (even though Reelin is expressed in non-CR cells,

tive spatial arrangements between amniotes, which may involve including interneurons) (Soriano and Del Rio, 2005; Villar-Cervino

the modiﬁcation of the production and migration program of neu- and Marin, 2012). However, the identiﬁcation of multiple subtypes

ronal subtypes resulting in the expansion of neurons along radial of CR cells with distinct molecular features naturally underscored

dimensions in mammals. the complexity of CR cells and raised a question of how and why

A second possibility is that mammalian-speciﬁc neuronal com- such diversity of CR cells has been created. Regarding this, two non-

ponents may impact the ultimate laminar and areal organization exclusive mechanisms can explain their diversity. One is that the

that characterizes the neocortex. A century after the original presence of speciﬁc morphogens in each pallial sector may intro-

description by (Retzius, 1893) and (Cajal, 1899), CR cells were duce a regional character to the CR cell subtypes. For example, the

brought to attention by their critical roles in instructing radial neu- medial pallium is the source of Wnts and Bmps, and the ventral pal-

ron migration and ‘inside-out’ six-layer neocortex formation (Rice lium expresses Sfrp2 caudally and Fgf8, 17, and 18 rostrally. These

and Curran, 2001; Tissir and Gofﬁnet, 2003). Although the orig- may induce differential gene expressions in regional CR cells. The

inal phenotype of the spontaneous mutant mice for Reelin was second explanation is that CR cells may represent a default state of

reported earlier (D’Arcangelo et al., 1995; Ogawa et al., 1995), the cortical progenitors; therefore, these neurons retain a wider molec-

precise mechanisms of Reelin action in neuronal migration have ular repertoire due to the higher number of accessible chromatin at

been unraveled only recently (Franco et al., 2011; Gil-Sanz et al., the earliest competent state. Progression of the corticogenesis pro-

2013; Sekine et al., 2012, 2014). Indeed, expression studies in chick, gram may restrict the conﬁguration of the chromatin and limit the

turtle, crocodile and lizard shows that Reelin-positive, CR-like neu- number of genes expressed in subsequent-born projection neurons.

rons are underrepresented in the sauropsid pallium, whereas the Are multiple origins and subtypes of CR cells a consequence or

number is increased in humans (Bernier et al., 1999, 2000; Cabrera- a cause of sauropsid-to-mammalian brain conversion? It is possi-

Socorro et al., 2007; Gofﬁnet et al., 1999; Meyer, 2010; Tissir et al., ble, that the neocortical evolution may itself require the increase in

2003). The correlation between an increase in the medial pallium both the number of CR cells and their molecular diversity. Pollard

during evolution also suggests a concerted role in the evolutionary et al. (2006) scanned ancestrally conserved genomic regions to

increase of CR cells (Meyer, 2010). In lizards, the cells express- search for regions that showed signiﬁcant acceleration of substitut-

ing p73 in the dorsal pallium appears much fewer than that of ions in the human lineage, and found that many of these human

Reelin-positive cells (Cabrera-Socorro et al., 2007), implying that accelerated regions (HARs) are associated with genes involved in

the regulation of these two genes in CR cells may be different in transcriptional regulation and neural development. In particular,

reptiles. The functional signiﬁcance of CR cells is supported by an a 118 bp HAR1 region showed the most accelerated change and is

experimental evidence in which Reelin-introduced COS7 cell were expressed speciﬁcally in CR cells in human embryonic neocortex

transplanted into quail cortical slices, which prompted radial ﬁbers (Pollard et al., 2006). This suggests that molecular heterogeneity

to extend long processes toward the pial surface, a character for of CR cells may be associated with new functions during neocor-

mammalian neocortical progenitors (Nomura et al., 2008). While tical evolution. Consistent with this view, the manipulation in the

these studies are indicative that the acquisition of CR cells was a number and distribution of CR cells can modify progenitor prop-

critical event in establishing a laminated neocortex system, it is erties in a region-speciﬁc manner, implying that CR cell subtypes

also noteworthy that reducing the number of CR cells in mice by may serve as mediators of early neocortical patterning (Griveau

Cre/+ loxp-stop-loxp-dta

genetic ablation (35% reduction in Wnt3a ; Rosa26 et al., 2010). As opposed to the projection neurons that have dis-

Cre/+

double heterozygous mice and 84% reduction in Wnt3a ; cerned functions in the neocortical circuit formation, the extent

Cre/+ loxp-stop-loxp-dta

DeltaNp73 ; Rosa26 triple heterozygous mice) of heterogeneity and functional repertoire of early-born neurons

results in an overall normal laminar organization at birth (Tissir is still largely unknown, partly because the molecular diversity of

et al., 2009; Yoshida et al., 2006). These results imply that the these subtypes has only been appreciated recently (Griveau et al.,

signiﬁcant increase in CR cell number and diversity during evolu- 2010; Hoerder-Suabedissen and Molnar, 2013; Kumamoto et al.,

tion may serve roles beyond lamination to instruct the neocortical 2013). Further investigations into the molecular functions of CR

cytoarchitecture. cells will provide insights into the ontogeny and elaboration of a

Interestingly, the binding sequences of Foxg1 to its target CR mammalian-speciﬁc neocortical circuit formation.

cell genes are only conserved in mammals (Kumamoto et al., 2013). Currently, the mechanisms of mammalian neocortical subtype

Therefore, the regulation of CR cells by Foxg1 in itself may have been speciﬁcation stand on the premise that the molecules and their

a novel acquisition of the mammalian species. Notably, the expres- activity identiﬁed in mice are generally conserved among mam-

sion of Foxg1 appears with a shorter delay to that of Emx2 in chick mals. However, the size of the neocortex differs substantially in

than in mice; Foxg1 is detectable as early as Hamburger–Hamilton different species ranging from soricomorpha to cetaceans (Catania

stage (HH) 6 in the chick anterior neural plate and is highly et al., 1999; Naumann et al., 2012). Taking this into consider-

expressed at HH8, whereas Emx2 expression is low at HH8 and ation, the regulation of the production of neocortical subtypes

increases after HH12 (Bell et al., 2001). In mouse, the onset of requires a developmental process in the broader context of evolu-

Foxg1 expression (5-somite stage) (Kobayashi et al., 2002; Lagutin tion that ultimately balances the numbers of functionally distinct

et al., 2003) follows that of Emx2 (3-somites) (Simeone et al., 1992; neurons among different species. Hence, such mechanisms must

Suda et al., 2001) expression. The differences in their expression utilize a system adaptable to changes in cortical size during mam-

timing may thus inﬂuence the early patterning of respective dor- malian evolution. For example, Foxg1 target transcription factors

sal and medial pallial territories (Fig. 1B), thereby contributing exhibit a caudal-to-rostral gradient expression within the pallium,

46 T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49

implying that the onset of Foxg1 expression induced by anterior Alcamo, E.A., Chirivella, L., Dautzenberg, M., Dobreva, G., Farinas, I., Grosschedl, R.,

McConnell, S.K., 2008. Satb2 regulates callosal projection neuron identity in the

FGF8 (Shimamura and Rubenstein, 1997) might repress early cell

developing cerebral cortex. Neuron 57, 364–377.

competence in an opposed rostral-to-caudal gradient, resulting in a

Anderson, J.C., Douglas, R.J., Martin, K.A., Nelson, J.C., 1994. Synaptic output of phys-

spatiotemporal switch from CR cell to DL neuron identity (Fig. 2C). iologically identiﬁed spiny stellate neurons in cat visual cortex. J. Comp. Neurol.

341, 16–24.

Therefore, the expansion of mammalian cortical size during evolu-

Anderson, S.A., Eisenstat, D.D., Shi, L., Rubenstein, J.L., 1997. Interneuron migra-

tion may have incorporated efﬁcient, compensatory mechanisms

tion from basal forebrain to neocortex: dependence on Dlx genes. Science 278,

to generate sufﬁcient numbers of CR cells prior to the onset of DL 474–476.

Arlotta, P., Molyneaux, B.J., Chen, J., Inoue, J., Kominami, R., Macklis, J.D., 2005.

neurogenesis, which requires CR cells for their radial migration.

Neuronal subtype-speciﬁc genes that control corticospinal motor neuron devel-

How is the neuronal number of other layer subtypes controlled?

opment in vivo. Neuron 45, 207–221.

Higher-order mammals, such as primates, have large gyrencephalic Assimacopoulos, S., Grove, E.A., Ragsdale, C.W., 2003. Identiﬁcation of a Pax6-

neocortex. Recent studies have shown that the disproportionate dependent epidermal growth factor family signaling source at the lateral edge

of the embryonic cerebral cortex. J. Neurosci. 23, 6399–6403.

expansion of neocortical surface area and neuron number during

Backman, M., Machon, O., Mygland, L., van den Bout, C.J., Zhong, W., Taketo, M.M.,

evolution relies on the acquisition of novel progenitor types and

Krauss, S., 2005. Effects of canonical Wnt signaling on dorso-ventral speciﬁcation

additional germinal zones including outer RGCs and SVZ (Betizeau of the mouse telencephalon. Dev. Biol. 279, 155–168.

Bardet, S.M., Ferran, J.L., Sanchez-Arrones, L., Puelles, L., 2010. Ontogenetic expres-

et al., 2013; Fietz et al., 2010; Geschwind and Rakic, 2013; Hansen

sion of sonic hedgehog in the chicken subpallium. Front. Neuroanat. 4, 28,

et al., 2010; Lui et al., 2011; Shitamukai et al., 2011). Therefore, the http://dx.doi.org/10.3389/fnana.2010.00028.

regulation of a switch from DL to UL neurogenesis will also require Bartolini, G., Ciceri, G., Marin, O., 2013. Integration of GABAergic interneurons into

cortical cell assemblies: lessons from embryos and adults. Neuron 79, 849–864.

a system that is adaptable to increases in cortical size, gestational

Bedogni, F., Hodge, R.D., Elsen, G.E., Nelson, B.R., Daza, R.A., Beyer, R.P., Bammler, T.K.,

period, cell cycle, and division modes during mammalian evolu-

Rubenstein, J.L., Hevner, R.F., 2010. Tbr1 regulates regional and laminar identity

tion (Fietz and Huttner, 2011; Lui et al., 2011). The mechanisms of postmitotic neurons in developing neocortex. Proc. Natl. Acad. Sci. U.S.A. 107,

13129–13134.

that balance the production of UL to DL neurogenesis await further

Belgard, T.G., Marques, A.C., Oliver, P.L., Abaan, H.O., Sirey, T.M., Hoerder-

investigation, including the segregation timing of their lineages

Suabedissen, A., Garcia-Moreno, F., Molnar, Z., Margulies, E.H., Ponting, C.P.,

(Franco et al., 2012; Guo et al., 2013). 2011. A transcriptomic atlas of mouse neocortical layers. Neuron 71, 605–616.

Belgard, T.G., Montiel, J.F., Wang, W.Z., Garcia-Moreno, F., Margulies, E.H., Ponting,

C.P., Molnar, Z., 2013. Adult pallium transcriptomes surprise in not reﬂecting

7. Conclusions

predicted homologies across diverse chicken and mouse pallial sectors. Proc.

Natl. Acad. Sci. U.S.A. 110, 13150–13155.

Bell, E., Ensini, M., Gulisano, M., Lumsden, A., 2001. Dynamic domains of gene expres-

The neocortical structure is specialized for processing an exten-

sion in the early avian forebrain. Dev. Biol. 236, 76–88.

sive range of information and complex behaviors that are unique

Bernard, A., Lubbers, L.S., Tanis, K.Q., Luo, R., Podtelezhnikov, A.A., Finney, E.M.,

to mammalian vertebrates. At molecular levels, the mechanisms McWhorter, M.M., Serikawa, K., Lemon, T., Morgan, R., Copeland, C., Smith, K.,

underlying the speciﬁcation of neuronal subtypes have begun to Cullen, V., Davis-Turak, J., Lee, C.K., Sunkin, S.M., Loboda, A.P., Levine, D.M., Stone,

D.J., Hawrylycz, M.J., Roberts, C.J., Jones, A.R., Geschwind, D.H., Lein, E.S., 2012.

unravel; however, that much remains to be explored about when

Transcriptional architecture of the primate neocortex. Neuron 73, 1083–1099.

and how these fate commitments takes place. Although this review

Bernier, B., Bar, I., D’Arcangelo, G., Curran, T., Gofﬁnet, A.M., 2000. Reelin mRNA

highlights the signiﬁcance of neocortical assembly in mammals, expression during embryonic brain development in the chick. J. Comp. Neurol.

422, 448–463.

these insights also imply that neuronal speciﬁcation and pattern-

Bernier, B., Bar, I., Pieau, C., Lambert De Rouvroit, C., Gofﬁnet, A.M., 1999. Reelin

ing may involve species-speciﬁc regulatory mechanisms in reptiles

mRNA expression during embryonic brain development in the turtle Emys orbic-

and birds. Of course, one cannot argue the presence of higher ularis. J. Comp. Neurol. 413, 463–479.

Betizeau, M., Cortay, V., Patti, D., Pﬁster, S., Gautier, E., Bellemin-Menard, A., Afanassi-

cognitive processing in birds and reptiles (Reiner and Northcutt,

eff, M., Huissoud, C., Douglas, R.J., Kennedy, H., Dehay, C., 2013. Precursor

2000) despite the lack of distinctive laminated cytoarchitecture.

diversity and complexity of lineage relationships in the outer subventricular

While an anatomically remote structure such as the DVR makes zone of the primate. Neuron 80, 442–457.

Bielle, F., Griveau, A., Narboux-Neme, N., Vigneau, S., Sigrist, M., Arber, S., Wassef,

the direct comparison of neuronal subtypes between mammals

M., Pierani, A., 2005. Multiple origins of Cajal–Retzius cells at the borders of the

and sauropsid brains devious, combinatorial approaches includ-

developing pallium. Nat. Neurosci. 8, 1002–1012.

ing molecular function and lineage analysis will eventually connect Britanova, O., de Juan Romero, C., Cheung, A., Kwan, K.Y., Schwark, M., Gyorgy, A.,

Vogel, T., Akopov, S., Mitkovski, M., Agoston, D., Sestan, N., Molnar, Z., Tarabykin,

their ontogeny. Detailed understanding of the roles of mammalian-

V., 2008. Satb2 is a postmitotic determinant for upper-layer neuron speciﬁcation

speciﬁc neuron population such as CR cells will likely provide new

in the neocortex. Neuron 57, 378–392.

insights into neocortical development. Taking into account all these Bruce, L.L., Neary, T.J., 1995a. Afferent projections to the lateral and dorsomedial

questions, future experiments addressing how the neocortex is hypothalamus in a lizard, Gekko gecko. Brain Behav. Evol. 46, 30–42.

Bruce, L.L., Neary, T.J., 1995b. Afferent projections to the ventromedial hypothalamic

established from an ancestral dorsal telencephalon will place the

nucleus in a lizard, Gekko gecko. Brain Behav. Evol. 46, 14–29.

critical piece of the puzzle concerning the functional signiﬁcance

Bulchand, S., Grove, E.A., Porter, F.D., Tole, S., 2001. LIM-homeodomain gene Lhx2

of the human neocortical circuit. regulates the formation of the cortical hem. Mech. Dev. 100, 165–175.

Cabrera-Socorro, A., Hernandez-Acosta, N.C., Gonzalez-Gomez, M., Meyer, G., 2007.

Comparative aspects of p73 and Reelin expression in Cajal–Retzius cells and the

Acknowledgements cortical hem in lizard, mouse and human. Brain Res. 1132, 59–70.

Cajal, S.R., 1899. Estudios sobre la corteza cerebral humana. Oxford University Press,

Oxford.

We thank T. Hirasawa and S. Kuratani (RIKEN CDB) for pro-

Catania, K.C., Lyon, D.C., Mock, O.B., Kaas, J.H., 1999. Cortical organization in shrews:

viding us with the neonate Chinese soft-shelled turtles (Pelodiscus

evidence from ﬁve species. J. Comp. Neurol. 410, 55–72.

sinensis). We thank all members of the Hanashima laboratory for Chen, B., Schaevitz, L.R., McConnell, S.K., 2005a. Fezl regulates the differentiation

and axon targeting of layer 5 subcortical projection neurons in cerebral cortex.

insightful comments and discussions. This study was supported

Proc. Natl. Acad. Sci. U.S.A. 102, 17184–17189.

through a Grant-in-Aid for Scientiﬁc Research on Innovative Areas

Chen, B., Wang, S.S., Hattox, A.M., Rayburn, H., Nelson, S.B., McConnell, S.K., 2008.

“Neural Diversity and Neocortical Organization” from the MEXT of The Fezf2-Ctip2 genetic pathway regulates the fate choice of subcortical projec-

tion neurons in the developing cerebral cortex. Proc. Natl. Acad. Sci. U.S.A. 105,

Japan (25123725) to C.H.

11382–11387.

Chen, C.C., Winkler, C.M., Pfenning, A.R., Jarvis, E.D., 2013. Molecular proﬁling of the

References developing avian telencephalon: regional timing and brain subdivision conti-

nuities. J. Comp. Neurol. 521, 3666–3701.

Chen, J.G., Rasin, M.R., Kwan, K.Y., Sestan, N., 2005b. Zfp312 is required for subcortical

Abellan, A., Medina, L., 2009. Subdivisions and derivatives of the chicken subpallium

axonal projections and dendritic morphology of deep-layer pyramidal neurons

based on expression of LIM and other regulatory genes and markers of neuron

of the cerebral cortex. Proc. Natl. Acad. Sci. U.S.A. 102, 17792–17797.

subpopulations during development. J. Comp. Neurol. 515, 465–501.

Cheung, A.F., Pollen, A.A., Tavare, A., DeProto, J., Molnar, Z., 2007. Comparative

Ahlgren, S., Vogt, P., Bronner-Fraser, M., 2003. Excess FoxG1 causes overgrowth of

aspects of cortical neurogenesis in vertebrates. J. Anat. 211, 164–176.

the neural tube. J. Neurobiol. 57, 337–349.

T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49 47

Chou, S.J., Perez-Garcia, C.G., Kroll, T.T., O’Leary, D.D., 2009. Lhx2 speciﬁes regional Gutin, G., Fernandes, M., Palazzolo, L., Paek, H., Yu, K., Ornitz, D.M., McConnell, S.K.,

fate in Emx1 lineage of telencephalic progenitors generating cerebral cortex. Hebert, J.M., 2006. FGF signalling generates ventral telencephalic cells indepen-

Nat. Neurosci. 12, 1381–1389. dently of SHH. Development 133, 2937–2946.

Chowdhury, T.G., Jimenez, J.C., Bomar, J.M., Cruz-Martin, A., Cantle, J.P., Portera- Hammarberg, C., 1895. Studien über Klinik und Pathologie der Idiotie nebst Unter-

Cailliau, C., 2010. Fate of Cajal–Retzius neurons in the postnatal mouse suchungen über die normale Anatomie der Hirnrinde. Upsala, Berlin.

neocortex. Front. Neuroanat. 4, 10. Han, W., Kwan, K.Y., Shim, S., Lam, M.M., Shin, Y., Xu, X., Zhu, Y., Li, M., Sestan, N., 2011.

Cooper, J.A., 2008. A mechanism for inside-out lamination in the neocortex. Trends TBR1 directly represses Fezf2 to control the laminar origin and development of

Neurosci. 31, 113–119. the corticospinal tract. Proc. Natl. Acad. Sci. U.S.A. 108, 3041–3046.

D’Arcangelo, G., Miao, G.G., Chen, S.C., Soares, H.D., Morgan, J.I., Curran, T., 1995. A Hanashima, C., Fernandes, M., Hebert, J.M., Fishell, G., 2007. The role of Foxg1 and

protein related to extracellular matrix proteins deleted in the mouse mutant dorsal midline signaling in the generation of Cajal–Retzius subtypes. J. Neurosci.

reeler. Nature 374, 719–723. 27, 11103–11111.

Danesin, C., Peres, J.N., Johansson, M., Snowden, V., Cording, A., Papalopulu, N., Hanashima, C., Li, S.C., Shen, L., Lai, E., Fishell, G., 2004. Foxg1 suppresses early cortical

Houart, C., 2009. Integration of telencephalic Wnt and hedgehog signaling center cell fate. Science 303, 56–59.

activities by Foxg1. Dev. Cell 16, 576–587. Hanashima, C., Shen, L., Li, S.C., Lai, E., 2002. Brain factor-1 controls the prolifer-

De Bergeyck, V., Naerhuyzen, B., Gofﬁnet, A.M., Lambert de Rouvroit, C., 1998. A ation and differentiation of neocortical progenitor cells through independent

panel of monoclonal antibodies against reelin, the extracellular matrix protein mechanisms. J. Neurosci. 22, 6526–6536.

defective in reeler mutant mice. J. Neurosci. Methods 82, 17–24. Hansen, D.V., Lui, J.H., Parker, P.R., Kriegstein, A.R., 2010. Neurogenic radial glia in

De la Rossa, A., Bellone, C., Golding, B., Vitali, I., Moss, J., Toni, N., Luscher, C., Jabaudon, the outer subventricular zone of human neocortex. Nature 464, 554–561.

D., 2013. In vivo reprogramming of circuit connectivity in postmitotic neocorti- Hardcastle, Z., Papalopulu, N., 2000. Distinct effects of XBF-1 in regulating the

cal neurons. Nat. Neurosci. 16, 193–200. cell cycle inhibitor p27(XIC1) and imparting a neural fate. Development 127,

Del Rio, J.A., Martinez, A., Fonseca, M., Auladell, C., Soriano, E., 1995. Glutamate- 1303–1314.

like immunoreactivity and fate of Cajal–Retzius cells in the murine cortex as Haug, H., 1987. Brain sizes, surfaces, and neuronal sizes of the cortex cerebri: a

identiﬁed with calretinin antibody. Cereb. Cortex 5, 13–21. stereological investigation of man and his variability and a comparison with

Dugas-Ford, J., Rowell, J.J., Ragsdale, C.W., 2012. Cell-type homologies and the origins some mammals (primates, whales, marsupials, insectivores, and one elephant).

of the neocortex. Proc. Natl. Acad. Sci. U.S.A. 109, 16974–16979. Am. J. Anat. 180, 126–142.

Eiraku, M., Watanabe, K., Matsuo-Takasaki, M., Kawada, M., Yonemura, S., Mat- Hevner, R.F., Daza, R.A., Rubenstein, J.L., Stunnenberg, H., Olavarria, J.F., Englund, C.,

sumura, M., Wataya, T., Nishiyama, A., Muguruma, K., Sasai, Y., 2008. 2003. Beyond laminar fate: toward a molecular classiﬁcation of cortical projec-

Self-organized formation of polarized cortical tissues from ESCs and its active tion/pyramidal neurons. Dev. Neurosci. 25, 139–151.

manipulation by extrinsic signals. Cell Stem Cell 3, 519–532. Hevner, R.F., Shi, L., Justice, N., Hsueh, Y., Sheng, M., Smiga, S., Bulfone, A., Gofﬁnet,

Fame, R.M., MacDonald, J.L., Macklis, J.D., 2011. Development, speciﬁcation, and A.M., Campagnoni, A.T., Rubenstein, J.L., 2001. Tbr1 regulates differentiation of

diversity of callosal projection neurons. Trends Neurosci. 34, 41–50. the preplate and layer 6. Neuron 29, 353–366.

Fernandez, A.S., Pieau, C., Reperant, J., Boncinelli, E., Wassef, M., 1998. Expression of Hirata, T., Suda, Y., Nakao, K., Narimatsu, M., Hirano, T., Hibi, M., 2004. Zinc ﬁnger

the Emx-1 and Dlx-1 homeobox genes deﬁne three molecularly distinct domains gene fez-like functions in the formation of subplate neurons and thalamocortical

in the telencephalon of mouse, chick, turtle and frog embryos: implications axons. Dev. Dyn. 230, 546–556.

for the evolution of telencephalic subdivisions in amniotes. Development 125, Hoerder-Suabedissen, A., Molnar, Z., 2013. Molecular diversity of early-born sub-

2099–2111. plate neurons. Cereb. Cortex 23, 1473–1483.

Fertuzinhos, S., Li, M., Kawasawa, Y.I., Ivic, V., Franjic, D., Singh, D., Crair, M., Sestan, Hou, P.S., Chuang, C.Y., Kao, C.F., Chou, S.J., Stone, L., Ho, H.N., Chien, C.L., Kuo,

N., 2014. Laminar and temporal expression dynamics of coding and noncoding H.C., 2013. LHX2 regulates the neural differentiation of human embryonic stem

RNAs in the mouse neocortex. Cell Rep. 6, 938–950. cells via transcriptional modulation of PAX6 and CER1. Nucleic Acids Res. 41,

Fietz, S.A., Huttner, W.B., 2011. Cortical progenitor expansion, self-renewal and neu- 7753–7770.

rogenesis – a polarized perspective. Curr. Opin. Neurobiol. 21, 23–35. Imayoshi, I., Shimogori, T., Ohtsuka, T., Kageyama, R., 2008. Hes genes and neu-

Fietz, S.A., Kelava, I., Vogt, J., Wilsch-Brauninger, M., Stenzel, D., Fish, J.L., Corbeil, D., rogenin regulate non-neural versus neural fate speciﬁcation in the dorsal

Riehn, A., Distler, W., Nitsch, R., Huttner, W.B., 2010. OSVZ progenitors of human telencephalic midline. Development 135, 2531–2541.

and ferret neocortex are epithelial-like and expand by integrin signaling. Nat. Inoue, F., Kurokawa, D., Takahashi, M., Aizawa, S., 2012. Gbx2 directly restricts Otx2

Neurosci. 13, 690–699. expression to forebrain and midbrain, competing with class III POU factors. Mol.

Franco, S.J., Gil-Sanz, C., Martinez-Garay, I., Espinosa, A., Harkins-Perry, S.R., Ramos, Cell. Biol. 32, 2618–2627.

C., Muller, U., 2012. Fate-restricted neural progenitors in the mammalian cere- Inoue, K., Terashima, T., Nishikawa, T., Takumi, T., 2004. Fez1 is layer-speciﬁcally

bral cortex. Science 337, 746–749. expressed in the adult mouse neocortex. Eur. J. Neurosci. 20, 2909–2916.

Franco, S.J., Martinez-Garay, I., Gil-Sanz, C., Harkins-Perry, S.R., Muller, U., 2011. Inoue, T., Nakamura, S., Osumi, N., 2000. Fate mapping of the mouse prosencephalic

Reelin regulates cadherin function via Dab1/Rap1 to control neuronal migration neural plate. Dev. Biol. 219, 373–383.

and lamination in the neocortex. Neuron 69, 482–497. Jarvis, E.D., Yu, J., Rivas, M.V., Horita, H., Feenders, G., Whitney, O., Jarvis, S.C., Jarvis,

Frantz, G.D., McConnell, S.K., 1996. Restriction of late cerebral cortical progenitors E.R., Kubikova, L., Puck, A.E., Siang-Bakshi, C., Martin, S., McElroy, M., Hara, E.,

to an upper-layer fate. Neuron 17, 55–61. Howard, J., Pfenning, A., Mouritsen, H., Chen, C.C., Wada, K., 2013. Global view

Garcia-Moreno, F., Lopez-Mascaraque, L., De Carlos, J.A., 2007. Origins and migratory of the functional molecular organization of the avian cerebrum: mirror images

routes of murine Cajal–Retzius cells. J. Comp. Neurol. 500, 419–432. and functional columns. J. Comp. Neurol. 521, 3614–3665.

Garda, A.L., Puelles, L., Rubenstein, J.L., Medina, L., 2002. Expression patterns of Judas,ˇ M., Sedmak, G., Pletikos, M., Jovanov-Miloseviˇ c,´ N., 2010. Populations of sub-

Wnt8b and Wnt7b in the chicken embryonic brain suggest a correlation with plate and interstitial neurons in fetal and adult human telencephalon. J. Anat.

forebrain patterning centers and morphogenesis. Neuroscience 113, 689–698. 217, 381–399.

Gaspard, N., Bouschet, T., Hourez, R., Dimidschstein, J., Naeije, G., van den Ameele, J., Kammandel, B., Chowdhury, K., Stoykova, A., Aparicio, S., Brenner, S., Gruss, P., 1999.

Espuny-Camacho, I., Herpoel, A., Passante, L., Schiffmann, S.N., Gaillard, A., Van- Distinct cis-essential modules direct the time-space pattern of the Pax6 gene

derhaeghen, P., 2008. An intrinsic mechanism of corticogenesis from embryonic activity. Dev. Biol. 205, 79–97.

stem cells. Nature 455, 351–357. Kang, W., Wong, L.C., Shi, S.H., Hebert, J.M., 2009. The transition from radial glial to

Geschwind, D.H., Rakic, P., 2013. Cortical evolution: judge the brain by its cover. intermediate progenitor cell is inhibited by FGF signaling during corticogenesis.

Neuron 80, 633–647. J. Neurosci. 29, 14571–14580.

Ghosh, A., Antonini, A., McConnell, S.K., Shatz, C.J., 1990. Requirement for subplate Kanold, P.O., Kara, P., Reid, R.C., Shatz, C.J., 2003. Role of subplate neurons in func-

neurons in the formation of thalamocortical connections. Nature 347, 179–181. tional maturation of visual cortical columns. Science 301, 521–525.

Gil-Sanz, C., Franco, S.J., Martinez-Garay, I., Espinosa, A., Harkins-Perry, S., Muller, U., Kim, A.S., Anderson, S.A., Rubenstein, J.L., Lowenstein, D.H., Pleasure, S.J., 2001. Pax-6

2013. Cajal–Retzius cells instruct neuronal migration by coincidence signaling regulates expression of SFRP-2 and Wnt-7b in the developing CNS. J. Neurosci.

between secreted and contact-dependent guidance cues. Neuron 79, 461–477. 21, RC132.

Gilbert, C.D., Wiesel, T.N., 1979. Morphology and intracortical projections of func- Kimura, J., Suda, Y., Kurokawa, D., Hossain, Z.M., Nakamura, M., Takahashi, M., Hara,

tionally characterised neurones in the cat visual cortex. Nature 280, 120–125. A., Aizawa, S., 2005. Emx2 and Pax6 function in cooperation with Otx2 and Otx1

Gofﬁnet, A.M., Bar, I., Bernier, B., Trujillo, C., Raynaud, A., Meyer, G., 1999. Reelin to develop caudal forebrain primordium that includes future archipallium. J.

expression during embryonic brain development in lacertilian lizards. J. Comp. Neurosci. 25, 5097–5108.

Neurol. 414, 533–550. Kleinjan, D.A., Seawright, A., Childs, A.J., van Heyningen, V., 2004. Conserved

Gorski, J.A., Talley, T., Qiu, M., Puelles, L., Rubenstein, J.L., Jones, K.R., 2002. Cortical elements in Pax6 intron 7 involved in (auto)regulation and alternative tran-

excitatory neurons and glia, but not GABAergic neurons, are produced in the scription. Dev. Biol. 265, 462–477.

Emx1-expressing lineage. J. Neurosci. 22, 6309–6314. Kobayashi, D., Kobayashi, M., Matsumoto, K., Ogura, T., Nakafuku, M., Shimamura,

Greig, L.C., Woodworth, M.B., Galazo, M.J., Padmanabhan, H., Macklis, J.D., 2013. K., 2002. Early subdivisions in the neural plate deﬁne distinct competence for

Molecular logic of neocortical projection neuron speciﬁcation, development and inductive signals. Development 129, 83–93.

diversity. Nat. Rev. Neurosci. 14, 755–769. Kostovic, I., Rakic, P., 1980. Cytology and time of origin of interstitial neurons in the

Griveau, A., Borello, U., Causeret, F., Tissir, F., Boggetto, N., Karaz, S., Pierani, A., 2010. white matter in infant and adult human and monkey telencephalon. J. Neuro-

A novel role for Dbx1-derived Cajal–Retzius cells in early regionalization of the cytol. 9, 219–242.

cerebral cortical neuroepithelium. PLoS Biol. 8, e1000440. Kumamoto, T., Toma, K., Gunadi McKenna, W.L., Kasukawa, T., Katzman, S., Chen,

Guo, C., Eckler, M.J., McKenna, W.L., McKinsey, G.L., Rubenstein, J.L., Chen, B., 2013. B., Hanashima, C., 2013. Foxg1 coordinates the switch from nonradially to radi-

Fezf2 expression identiﬁes a multipotent progenitor for neocortical projection ally migrating glutamatergic subtypes in the neocortex through spatiotemporal

neurons, astrocytes, and oligodendrocytes. Neuron 80, 1167–1174. repression. Cell Rep. 3, 931–945.

48 T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49

Kurokawa, D., Ohmura, T., Sakurai, Y., Inoue, K., Suda, Y., Aizawa, S., 2014. Otx2 Molyneaux, B.J., Arlotta, P., Hirata, T., Hibi, M., Macklis, J.D., 2005. Fezl is required

expression in anterior neuroectoderm and forebrain/midbrain is directed by for the birth and speciﬁcation of corticospinal motor neurons. Neuron 47,

more than six enhancers. Dev. Biol. 387, 203–213. 817–831.

Kurokawa, D., Takasaki, N., Kiyonari, H., Nakayama, R., Kimura-Yoshida, C., Matsuo, Montiel, J.F., Molnar, Z., 2013. The impact of gene expression analysis on evolving

I., Aizawa, S., 2004. Regulation of Otx2 expression and its functions in mouse views of avian brain organization. J. Comp. Neurol. 521, 3604–3613.

epiblast and anterior neuroectoderm. Development 131, 3307–3317. Montiel, J.F., Wang, W.Z., Oeschger, F.M., Hoerder-Suabedissen, A., Tung, W.L.,

Kwan, K.Y., Lam, M.M., Johnson, M.B., Dube, U., Shim, S., Rasin, M.R., Sousa, A.M., Fer- Garcia-Moreno, F., Holm, I.E., Villalon, A., Molnar, Z., 2011. Hypothesis on the

tuzinhos, S., Chen, J.G., Arellano, J.I., Chan, D.W., Pletikos, M., Vasung, L., Rowitch, dual origin of the mammalian subplate. Front. Neuroanat. 5, 25.

D.H., Huang, E.J., Schwartz, M.L., Willemsen, R., Oostra, B.A., Rakic, P., Heffer, M., Monuki, E.S., Porter, F.D., Walsh, C.A., 2001. Patterning of the dorsal tele-

Kostovic, I., Judas, M., Sestan, N., 2012. Species-dependent posttranscriptional ncephalon and cerebral cortex by a roof plate-Lhx2 pathway. Neuron 32,

regulation of NOS1 by FMRP in the developing cerebral cortex. Cell 149, 899–911. 591–604.

Kwan, K.Y., Lam, M.M., Krsnik, Z., Kawasawa, Y.I., Lefebvre, V., Sestan, N., 2008. SOX5 Muzio, L., Di Benedetto, B., Stoykova, A., Boncinelli, E., Gruss, P., Mallamaci, A., 2002.

postmitotically regulates migration, postmigratory differentiation, and projec- Emx2 and Pax6 control regionalization of the pre-neuronogenic cortical pri-

tions of subplate and deep-layer neocortical neurons. Proc. Natl. Acad. Sci. U.S.A. mordium. Cereb. Cortex 12, 129–139.

105, 16021–16026. Muzio, L., Mallamaci, A., 2005. Foxg1 conﬁnes Cajal–Retzius neuronogenesis and

Lagutin, O.V., Zhu, C.C., Kobayashi, D., Topczewski, J., Shimamura, K., Puelles, L., Rus- hippocampal morphogenesis to the dorsomedial pallium. J. Neurosci. 25,

sell, H.R., McKinnon, P.J., Solnica-Krezel, L., Oliver, G., 2003. Six3 repression of 4435–4441.

Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain Naumann, R.K., Anjum, F., Roth-Alpermann, C., Brecht, M., 2012. Cytoarchitecture,

development. Genes Dev. 17, 368–379. areas, and neuron numbers of the Etruscan shrew cortex. J. Comp. Neurol. 520,

Lai, T., Jabaudon, D., Molyneaux, B.J., Azim, E., Arlotta, P., Menezes, J.R., Macklis, J.D., 2512–2530.

2008. SOX5 controls the sequential generation of distinct corticofugal neuron Nieto, M., Monuki, E.S., Tang, H., Imitola, J., Haubst, N., Khoury, S.J., Cunningham, J.,

subtypes. Neuron 57, 232–247. Gotz, M., Walsh, C.A., 2004. Expression of Cux-1 and Cux-2 in the subventric-

Lewis, B., 1878. On the comparative structure of the cortex cerebri. Brain 1, 79–96. ular zone and upper layers II–IV of the cerebral cortex. J. Comp. Neurol. 479,

Louvi, A., Yoshida, M., Grove, E.A., 2007. The derivatives of the Wnt3a lineage in the 168–180.

central nervous system. J. Comp. Neurol. 504, 550–569. Noctor, S.C., Flint, A.C., Weissman, T.A., Dammerman, R.S., Kriegstein, A.R., 2001.

Ludwig, J., Weseloh, R., Karschin, C., Liu, Q., Netzer, R., Engeland, B., Stansfeld, C., Neurons derived from radial glial cells establish radial units in neocortex. Nature

Pongs, O., 2000. Cloning and functional expression of rat eag2, a new mem- 409, 714–720.

ber of the ether-a-go-go family of potassium channels and comparison of its Nomura, T., Gotoh, H., Ono, K., 2013. Changes in the regulation of cortical neurogene-

distribution with that of eag1. Mol. Cell. Neurosci. 16, 59–70. sis contribute to encephalization during amniote brain evolution. Nat. Commun.

Lui, J.H., Hansen, D.V., Kriegstein, A.R., 2011. Development and evolution of the 4, 2206.

human neocortex. Cell 146, 18–36. Nomura, T., Takahashi, M., Hara, Y., Osumi, N., 2008. Patterns of neurogenesis and

Lund, J.S., Henry, G.H., MacQueen, C.L., Harvey, A.R., 1979. Anatomical organization amplitude of Reelin expression are essential for making a mammalian-type

of the primary visual cortex (area 17) of the cat. A comparison with area 17 of cortex. PLoS ONE 3, e1454.

the macaque monkey. J. Comp. Neurol. 184, 599–618. Ogawa, M., Miyata, T., Nakajima, K., Yagyu, K., Seike, M., Ikenaka, K., Yamamoto, H.,

Luskin, M.B., Pearlman, A.L., Sanes, J.R., 1988. Cell lineage in the cerebral cortex of Mikoshiba, K., 1995. The reeler gene-associated antigen on Cajal–Retzius neu-

the mouse studied in vivo and in vitro with a recombinant retrovirus. Neuron 1, rons is a crucial molecule for laminar organization of cortical neurons. Neuron

635–647. 14, 899–912.

Mangale, V.S., Hirokawa, K.E., Satyaki, P.R., Gokulchandran, N., Chikbire, S., Subra- Oliver, G., Wehr, R., Jenkins, N.A., Copeland, N.G., Cheyette, B.N., Hartenstein, V.,

manian, L., Shetty, A.S., Martynoga, B., Paul, J., Mai, M.V., Li, Y., Flanagan, L.A., Zipursky, S.L., Gruss, P., 1995. Homeobox genes and connective tissue patterning.

Tole, S., Monuki, E.S., 2008. Lhx2 selector activity speciﬁes cortical identity and Development 121, 693–705.

suppresses hippocampal organizer fate. Science 319, 304–309. Pani, A.M., Mullarkey, E.E., Aronowicz, J., Assimacopoulos, S., Grove, E.A., Lowe,

Manuel, M., Martynoga, B., Yu, T., West, J.D., Mason, J.O., Price, D.J., 2010. The tran- C.J., 2012. Ancient deuterostome origins of vertebrate brain signalling centres.

scription factor Foxg1 regulates the competence of telencephalic cells to adopt Nature 483, 289–294.

subpallial fates in mice. Development 137, 487–497. Parr, B.A., Shea, M.J., Vassileva, G., McMahon, A.P., 1993. Mouse Wnt genes exhibit

Marin-Padilla, M., 1998. Cajal–Retzius cells and the development of the neocortex. discrete domains of expression in the early embryonic CNS and limb buds.

Trends Neurosci. 21, 64–71. Development 119, 247–261.

Martin, K.A., Whitteridge, D., 1984. Form, function and intracortical projections of Pollard, K.S., Salama, S.R., Lambert, N., Lambot, M.A., Coppens, S., Pedersen, J.S., Katz-

spiny neurones in the striate visual cortex of the cat. J. Physiol. 353, 463–504. man, S., King, B., Onodera, C., Siepel, A., Kern, A.D., Dehay, C., Igel, H., Ares Jr., M.,

Martynoga, B., Morrison, H., Price, D.J., Mason, J.O., 2005. Foxg1 is required for Vanderhaeghen, P., Haussler, D., 2006. An RNA gene expressed during cortical

speciﬁcation of ventral telencephalon and region-speciﬁc regulation of dorsal development evolved rapidly in humans. Nature 443, 167–172.

telencephalic precursor proliferation and apoptosis. Dev. Biol. 283, 113–127. Price, D.J., Aslam, S., Tasker, L., Gillies, K., 1997. Fates of the earliest generated cells

Maruoka, H., Kubota, K., Kurokawa, R., Tsuruno, S., Hosoya, T., 2011. Periodic organi- in the developing murine neocortex. J. Comp. Neurol. 377, 414–422.

zation of a major subtype of pyramidal neurons in neocortical layer V. J. Neurosci. Price, J., Thurlow, L., 1988. Cell lineage in the rat cerebral cortex: a study using

31, 18522–18542. retroviral-mediated gene transfer. Development 104, 473–482.

McConnell, S.K., 1988. Fates of visual cortical neurons in the ferret after isochronic Puelles, L., 2011. Pallio-pallial tangential migrations and growth signaling: new

and heterochronic transplantation. J. Neurosci. 8, 945–974. scenario for cortical evolution? Brain Behav. Evol. 78, 108–127.

McConnell, S.K., Kaznowski, C.E., 1991. Cell cycle dependence of laminar determi- Puelles, L., Kuwana, E., Puelles, E., Bulfone, A., Shimamura, K., Keleher, J., Smiga, S.,

nation in developing neocortex. Science 254, 282–285. Rubenstein, J.L., 2000. Pallial and subpallial derivatives in the embryonic chick

McEvilly, R.J., de Diaz, M.O., Schonemann, M.D., Hooshmand, F., Rosenfeld, M.G., and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1,

2002. Transcriptional regulation of cortical neuron migration by POU domain Nkx-2.1, Pax-6, and Tbr-1. J. Comp. Neurol. 424, 409–438.

factors. Science 295, 1528–1532. Rakic, P., 1988. Speciﬁcation of cerebral cortical areas. Science 241, 170–176.

McKenna, W.L., Betancourt, J., Larkin, K.A., Abrams, B., Guo, C., Rubenstein, J.L., Chen, Rakic, P., 2009. Evolution of the neocortex: a perspective from developmental biol-

B., 2011. Tbr1 and Fezf2 regulate alternate corticofugal neuronal identities dur- ogy. Nat. Rev. Neurosci. 10, 724–735.

ing neocortical development. J. Neurosci. 31, 549–564. Rallu, M., Machold, R., Gaiano, N., Corbin, J.G., McMahon, A.P., Fishell, G.,

Medina, L., Legaz, I., Gonzalez, G., De Castro, F., Rubenstein, J.L., Puelles, L., 2004. 2002. Dorsoventral patterning is established in the telencephalon of

Expression of Dbx1, Neurogenin 2, Semaphorin 5A, Cadherin 8, and Emx1 distin- mutants lacking both Gli3 and Hedgehog signaling. Development 129, 4963–

guish ventral and lateral pallial histogenetic divisions in the developing mouse 4974.

claustroamygdaloid complex. J. Comp. Neurol. 474, 504–523. Regad, T., Roth, M., Bredenkamp, N., Illing, N., Papalopulu, N., 2007. The neural

Meyer, G., 2010. Building a human cortex: the evolutionary differentiation of progenitor-specifying activity of FoxG1 is antagonistically regulated by CKI and

Cajal–Retzius cells and the cortical hem. J. Anat. 217, 334–343. FGF. Nat. Cell Biol. 9, 531–540.

Meyer, G., Gofﬁnet, A.M., Fairen, A., 1999. What is a Cajal–Retzius cell? A reassess- Reid, C.B., Liang, I., Walsh, C., 1995. Systematic widespread clonal organization in

ment of a classical cell type based on recent observations in the developing cerebral cortex. Neuron 15, 299–310.

neocortex. Cereb. Cortex 9, 765–775. Reiner, A., Northcutt, R.G., 2000. Succinic dehydrogenase histochemistry reveals the

Meyer, G., Perez-Garcia, C.G., Abraham, H., Caput, D., 2002. Expression of p73 and location of the putative primary visual and auditory areas within the dorsal

Reelin in the developing human cortex. J. Neurosci. 22, 4973–4986. ventricular ridge of Sphenodon punctatus. Brain Behav. Evol. 55, 26–36.

Meynert, T., 1868. Der Bau der Großhirnrinde und seine örtlichen Verschieden- Retzius, G., 1893. Die Cajal’schen Zellen der Grosshirnrinde beim Menschen und bei

heiten nebst einem pathologisch-anatomischen Korollarium. Vierteljahresschr. Säugetieren. Biologische Untersuchungen. Neue Folge 5, 1–8.

Psychiatr. Rice, D.S., Curran, T., 2001. Role of the reelin signaling pathway in central nervous

Millet, S., Campbell, K., Epstein, D.J., Losos, K., Harris, E., Joyner, A.L., 1999. A role for system development. Annu. Rev. Neurosci. 24, 1005–1039.

Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature Roth, M., Bonev, B., Lindsay, J., Lea, R., Panagiotaki, N., Houart, C., Papalopulu, N., 2010.

401, 161–164. FoxG1 and TLE2 act cooperatively to regulate ventral telencephalon formation.

Molnar, Z., Cheung, A.F., 2006. Towards the classiﬁcation of subpopulations of layer Development 137, 1553–1562.

V pyramidal projection neurons. Neurosci. Res. 55, 105–115. Rouaux, C., Arlotta, P., 2013. Direct lineage reprogramming of post-mitotic callosal

Molyneaux, B.J., Arlotta, P., Fame, R.M., MacDonald, J.L., MacQuarrie, K.L., Mack- neurons into corticofugal neurons in vivo. Nat. Cell Biol. 15, 214–221.

lis, J.D., 2009. Novel subtype-speciﬁc genes identify distinct subpopulations of Roy, A., Gonzalez-Gomez, M., Pierani, A., Meyer, G., Tole, S., 2013. Lhx2 regulates the

callosal projection neurons. J. Neurosci. 29, 12343–12354. development of the forebrain hem system. Cereb. Cortex 24, 1361–1372.

T. Kumamoto, C. Hanashima / Neuroscience Research 86 (2014) 37–49 49

Saganich, M.J., Vega-Saenz de Miera, E., Nadal, M.S., Baker, H., Coetzee, W.A., Rudy, Suda, Y., Matsuo, I., Aizawa, S., 1997. Cooperation between Otx1 and Otx2 genes in

B., 1999. Cloning of components of a novel subthreshold-activating K(+) chan- developmental patterning of rostral brain. Mech. Dev. 69, 125–141.

nel with a unique pattern of expression in the cerebral cortex. J. Neurosci. 19, Suzuki, I.K., Kawasaki, T., Gojobori, T., Hirata, T., 2012. The temporal sequence of the

10789–10802. mammalian neocortical neurogenetic program drives mediolateral pattern in

Sahara, S., O’Leary, D.D., 2009. Fgf10 regulates transition period of cortical stem the chick pallium. Dev. Cell 22, 863–870.

cell differentiation to radial glia controlling generation of neurons and basal Takiguchi-Hayashi, K., Sekiguchi, M., Ashigaki, S., Takamatsu, M., Hasegawa, H.,

progenitors. Neuron 63, 48–62. Suzuki-Migishima, R., Yokoyama, M., Nakanishi, S., Tanabe, Y., 2004. Generation

Schaeren-Wiemers, N., Andre, E., Kapfhammer, J.P., Becker-Andre, M., 1997. The of reelin-positive marginal zone cells from the caudomedial wall of telencephalic

expression pattern of the orphan nuclear receptor RORbeta in the develop- vesicles. J. Neurosci. 24, 2286–2295.

ing and adult rat nervous system suggests a role in the processing of sensory Tao, W., Lai, E., 1992. Telencephalon-restricted expression of BF-1, a new mem-

information and in circadian rhythm. Eur. J. Neurosci. 9, 2687–2701. ber of the HNF-3/fork head gene family, in the developing rat brain. Neuron 8,

Sekine, K., Kawauchi, T., Kubo, K., Honda, T., Herz, J., Hattori, M., Kinashi, T., Naka- 957–966.

jima, K., 2012. Reelin controls neuronal positioning by promoting cell-matrix Teissier, A., Griveau, A., Vigier, L., Piolot, T., Borello, U., Pierani, A., 2010. A novel tran-

adhesion via inside-out activation of integrin alpha5beta1. Neuron 76, 353–369. sient glutamatergic population migrating from the pallial–subpallial boundary

Sekine, K., Kubo, K., Nakajima, K., 2014. How does Reelin control neuronal migration contributes to neocortical development. J. Neurosci. 30, 10563–10574.

and layer formation in the developing mammalian neocortex? Neurosci. Res., Teissier, A., Waclaw, R.R., Griveau, A., Campbell, K., Pierani, A., 2012. Tangentially

http://dx.doi.org/10.1016/j.neures.2014.06.004. migrating transient glutamatergic neurons control neurogenesis and mainte-

Seoane, J., Le, H.V., Shen, L., Anderson, S.A., Massague, J., 2004. Integration of Smad nance of cerebral cortical progenitor pools. Cereb. Cortex 22, 403–416.

and forkhead pathways in the control of neuroepithelial and glioblastoma cell Theil, T., Aydin, S., Koch, S., Grotewold, L., Ruther, U., 2002. Wnt and Bmp signalling

proliferation. Cell 117, 211–223. cooperatively regulate graded Emx2 expression in the dorsal telencephalon.

Shen, Q., Wang, Y., Dimos, J.T., Fasano, C.A., Phoenix, T.N., Lemischka, I.R., Ivanova, Development 129, 3045–3054.

N.B., Stifani, S., Morrisey, E.E., Temple, S., 2006. The timing of cortical neurogen- Tissir, F., Gofﬁnet, A.M., 2003. Reelin and brain development. Nat. Rev. Neurosci. 4,

esis is encoded within lineages of individual progenitor cells. Nat. Neurosci. 9, 496–505.

743–751. Tissir, F., Lambert De Rouvroit, C., Sire, J.Y., Meyer, G., Gofﬁnet, A.M., 2003. Reelin

Shimamura, K., Hartigan, D.J., Martinez, S., Puelles, L., Rubenstein, J.L., 1995. Longi- expression during embryonic brain development in Crocodylus niloticus. J. Comp.

tudinal organization of the anterior neural plate and neural tube. Development Neurol. 457, 250–262.

121, 3923–3933. Tissir, F., Ravni, A., Achouri, Y., Riethmacher, D., Meyer, G., Gofﬁnet, A.M., 2009.

Shimamura, K., Rubenstein, J.L., 1997. Inductive interactions direct early regional- DeltaNp73 regulates neuronal survival in vivo. Proc. Natl. Acad. Sci. U.S.A. 106,

ization of the mouse forebrain. Development 124, 2709–2718. 16871–16876.

Shitamukai, A., Konno, D., Matsuzaki, F., 2011. Oblique radial glial divisions in the Toresson, H., Martinez-Barbera, J.P., Bardsley, A., Caubit, X., Krauss, S., 1998. Con-

developing mouse neocortex induce self-renewing progenitors outside the ger- servation of BF-1 expression in amphioxus and zebraﬁsh suggests evolutionary

minal zone that resemble primate outer subventricular zone progenitors. J. ancestry of anterior cell types that contribute to the vertebrate telencephalon.

Neurosci. 31, 3683–3695. Dev. Genes Evol. 208, 431–439.

Simeone, A., Gulisano, M., Acampora, D., Stornaiuolo, A., Rambaldi, M., Boncinelli, E., Ulinski, P.S., 1986. Organization of corticogeniculate projections in the turtle, Pseude-

1992. Two vertebrate homeobox genes related to the Drosophila empty spiracles mys scripta. J. Comp. Neurol. 254, 529–542.

gene are expressed in the embryonic cerebral cortex. EMBO J. 11, 2541–2550. Villar-Cervino, V., Marin, O., 2012. Cajal–Retzius cells. Curr. Biol. 22, R179.

Smart, I.H., Dehay, C., Giroud, P., Berland, M., Kennedy, H., 2002. Unique morpho- von Frowein, J., Campbell, K., Gotz, M., 2002. Expression of Ngn1, Ngn2, Cash1, Gsh2

logical features of the proliferative zones and postmitotic compartments of the and Sfrp1 in the developing chick telencephalon. Mech. Dev. 110, 249–252.

neural epithelium giving rise to striate and extrastriate cortex in the monkey. von Frowein, J., Wizenmann, A., Götz, M., 2006. The transcription factors Emx1 and

Cereb. Cortex 12, 37–53. Emx2 suppress choroid plexus development and promote neuroepithelial cell

Soda, T., Nakashima, R., Watanabe, D., Nakajima, K., Pastan, I., Nakanishi, S., 2003. fate. Dev. Biol. 296, 239–252.

Segregation and coactivation of developing neocortical layer 1 neurons. J. Neu- Walsh, C., Cepko, C.L., 1988. Clonally related cortical cells show several migration

rosci. 23, 6272–6279. patterns. Science 241, 1342–1345.

Sommer, L., Ma, Q., Anderson, D.J., 1996. Neurogenins, a novel family of Walsh, C., Cepko, C.L., 1992. Widespread dispersion of neuronal clones across func-

atonal-related bHLH transcription factors, are putative mammalian neuronal tional regions of the cerebral cortex. Science 255, 434–440.

determination genes that reveal progenitor cell heterogeneity in the developing Yoneshima, H., Yamasaki, S., Voelker, C.C., Molnar, Z., Christophe, E., Audinat, E.,

CNS and PNS. Mol. Cell. Neurosci. 8, 221–241. Takemoto, M., Nishiwaki, M., Tsuji, S., Fujita, I., Yamamoto, N., 2006. Er81 is

Soriano, E., Del Rio, J.A., 2005. The cells of Cajal–Retzius: still a mystery one century expressed in a subpopulation of layer 5 neurons in rodent and primate neocor-

after. Neuron 46, 389–394. tices. Neuroscience 137, 401–412.

Srinivasan, K., Leone, D.P., Bateson, R.K., Dobreva, G., Kohwi, Y., Kohwi-Shigematsu, Yoshida, M., Assimacopoulos, S., Jones, K.R., Grove, E.A., 2006. Massive loss of

T., Grosschedl, R., McConnell, S.K., 2012. A network of genetic repression and Cajal–Retzius cells does not disrupt neocortical layer order. Development 133,

derepression speciﬁes projection fates in the developing neocortex. Proc. Natl. 537–545.

Acad. Sci. U.S.A. 109, 19071–19078. Yoshimura, Y., Dantzker, J.L., Callaway, E.M., 2005. Excitatory cortical neurons form

Staiger, J.F., Flagmeyer, I., Schubert, D., Zilles, K., Kotter, R., Luhmann, H.J., 2004. ﬁne-scale functional networks. Nature 433, 868–873.

Functional diversity of layer IV spiny neurons in rat somatosensory cortex: quan- Yu, Y.C., Bultje, R.S., Wang, X., Shi, S.H., 2009. Speciﬁc synapses develop preferentially

titative morphology of electrophysiologically characterized and biocytin labeled among sister excitatory neurons in the neocortex. Nature 458, 501–504.

cells. Cereb. Cortex 14, 690–701. Yu, Y.C., He, S., Chen, S., Fu, Y., Brown, K.N., Yao, X.H., Ma, J., Gao, K.P., Sosinsky, G.E.,

Striedter, G.F., Marchant, T.A., Beydler, S., 1998. The neostriatum develops as part of Huang, K., Shi, S.H., 2012. Preferential electrical coupling regulates neocortical

the lateral pallium in birds. J. Neurosci. 18, 5839–5849. lineage-dependent microcircuit assembly. Nature 486, 113–117.

Stumm, R.K., Zhou, C., Ara, T., Lazarini, F., Dubois-Dalcq, M., Nagasawa, T., Hollt, Yun, K., Potter, S., Rubenstein, J.L., 2001. Gsh2 and Pax6 play complementary roles

V., Schulz, S., 2003. CXCR4 regulates interneuron migration in the developing in dorsoventral patterning of the mammalian telencephalon. Development 128,

neocortex. J. Neurosci. 23, 5123–5130. 193–205.

Suda, Y., Hossain, Z.M., Kobayashi, C., Hatano, O., Yoshida, M., Matsuo, I., Aizawa, S., Zhong, Y., Takemoto, M., Fukuda, T., Hattori, Y., Murakami, F., Nakajima, D.,

2001. Emx2 directs the development of diencephalon in cooperation with Otx2. Nakayama, M., Yamamoto, N., 2004. Identiﬁcation of the genes that are

Development 128, 2433–2450. expressed in the upper layers of the neocortex. Cereb. Cortex 14, 1144–1152.