Rorb

Lhx2

Cux1/2 Cdh8

Lmo4, EphA7, SCPN CThPN CPN

Satb2

Bhlhb5 +

+

Couptf1 Low expression Couptf1

Tbr1 Tbr1

; Tbr1 ; Satb2 +

+ + + Limch1, Btg1 + Sox5

Cdh6

Cux1, Cux2, Inhba, MATURE POSTMITOTIC Fezf2/Ctip2/Otx1 Tcrb, Dkk3, Gfra2 Ctip2 Tbr1 Satb2 Ctip2 Ctip2

Bhlhb5, Couptf1,

Plxnd1, EphrinA5, Cux1/2 Satb2

V VI I II/III IV WM SP

Satb2, Lmo4, Hspb3, Lpl

Bhlhb5 Tbr1 High expression

Visual Sensory Motor Sox5 Bhlhb5, Couptf1,

layer II/III

IMMATURE layer V-VI POSTMITOTIC Fezf2/Ctip2 Plxnd1, Cdh6 Harvard Harvard 2

XX X

Cux2 Tbr2 Callosal Projection Neurons (CPN) SVZ CC Department of 4 P4 PROGENITORS

Subtype speci city not known Cux2

XX X Fezf2 VI CP VZ MZ CP V VI SVZ VZ

refines as neurons differentiate delineate projection neuron identity

Lhx2

Ngn2

Couptf1

Sox6 Crym, Motor Diap3, Igfbp4,

(CSMN) S100a10 Pax6

Combinatorial transcription factor programs progressively

VZ PROGENITORS Emx2 Subtype-speci c Initially overlapping expression of controls over subtype identity Bcl6 Cdh6, Bhlhb5, Sensory SP IV GC SCPN CThPN DL CPN UL CPN 1,2 E13.5 E15.5 Clim1,Csmn1, Cdh13 Fezf2, Ctip2, Sox5, Otx1, I IV V VI SP II/III Odz3 Visual (CTPN) Bhlhb5, WM Lix1, Id2, These authors contributed equally to this work 5 P4 Lmo4 Bhlhb5 I II/III IV V VI SP and Jeffrey D. Macklis and Jeffrey VZ SVZ P4 3,4 OT Subcerebral Projection Neurons (SCPN) E15.5 M1 M1 S1 A1 I IV V VI SP V1 SC SC VZ SVZ XX XXX X Id2, E14.5 Arnold R. Kriegstein, Epha7 1,2,5 Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research; Center of Regeneration Medicine and Stem Cell Research; Eli and Edythe Broad 3 V VI I SP Lmo4 Bhlhb5 VZ SVZ Couptf1, Sensory Motor EphrinA5 E15.5 Fog2, FoxP2, N b Tbr1, Sox5, Darpp32, Tle4, Visual XXXXX X Couptf1 that demarcate cortical areas MZ CP SP Astrocyte oRG Migrating immature neurons IP SVZ VZ Luciano Custo Greig, E12.5 E13.5 1,2,5 Sp8 Couptf1 Pax6 Emx2 PP VZ SCPN Layer IV GC UL CPN RG VP VP dLG dLG E12.5 Expression gradients in the VZ and CP evolve into discrete domains DL CPN CR SP CThPN NE Corticothalamic Projection Neurons (CThPN) Distinct progenitor populations generate projection neurons in an “inside-out” fashion E10.5 E11.5 Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; University, Stem Cell Institute, Harvard Department of Stem Cell and Regenerative Biology Harvard SnapShot: Cortical Development Mollie B. Woodworth, 1 Neurology, University of California, San Francisco, CA 94143, USA; Neurology, Medical School, Boston, MA 02115, USA; SnapShot: AUTHOR XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX AFFILIATION

9181 Cell Cell 151???,, November??MONTH?? 9, 2012??DATE??, ©2012 200? Elsevier ©200? Inc. Elsevier DOI http://dx.doi.org/ Inc. DOI XXXXXXXXX 10.1016/j.cell.2012.10.004 See online version Seefor legend online versionand references. for ??????. SnapShot: Cortical Development Mollie B. Woodworth,1,2,5 Luciano Custo Greig,1,2,5 Arnold R. Kriegstein,3,4 and Jeffrey D. Macklis1,2 1Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; 2Harvard Medical School, Boston, MA 02115, USA; 3Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research; 4Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; 5These authors contributed equally to this work

This SnapShot summarizes current knowledge of mammalian cortical development, with a particular focus on the molecular controls that orchestrate the stepwise decisions leading from multiple types of undifferentiated forebrain progenitors to fully mature projection neurons with correctly targeted axons and carefully elaborated dendritic trees, as well as appropriate electrophysiology and gene expression, reflective of precise subtype and area identity.

Neocortical Progenitors Early in development, the telencephalic wall is composed of undifferentiated neuroepithelial (NE) cells, which give rise to diverse progenitor populations. Radial glial cells (RG) divide asymmetrically to self-renew and generate intermediate progenitor (IP) cells or neurons. IP cells divide symmetrically to produce two neurons. In the mouse, small numbers of neurons are produced by radial glia-like (oRG) cells, but oRG cells are abundant in the outer SVZ of human fetal cortex, where they generate transit-amplifying cells that in turn produce most cortical neurons.

Projection Neuron Diversity Specific subtypes of neocortical projection neurons are generated by neural progenitors during distinct temporal windows, beginning in mice at? E11.5 and continuing through late embryonic development. These young postmitotic neurons migrate away from the ventricular zone to populate progressively more superficial positions in the cortical plate. Projection neurons can be classified on the basis of their mature axonal projections: corticothalamic projection neurons (CThPN) are located in layer VI and send axons to thala- mus; subcerebral projection neurons (SCPN) are located in layer V and send axons to optic tectum, brainstem, or spinal cord; and callosal projection neurons (CPN) are located in layers II/III, V, and VI and send axons to contralateral cortex. Importantly, neurons of each subtype are further specialized based on their positions in specific cortical areas. For example, CThPN establish area-specific connections with thalamic nuclei (motor cortex CThPN with VL; sensory cortex CThPN with VP; visual cortex CThPN with dLG).

Molecular Controls over Subtype and Area Identity Both subtype and area identity are specified in a stepwise fashion, with early overlapping expression of critical controls resolving over the course of development to specific subtypes and areas. Area identity begins to be imparted embryonically by smooth gradients of transcription factors in progenitors and postmitotic neurons, but during the first postnatal week, expression of critical controls, such as Lmo4 and Bhlhb5, becomes restricted to domains that sharply delineate cortical areas. Similarly, subtype identity is progressively specified, as molecular controls that are initially coexpressed by newly generated postmitotic neurons later refine to a single subtype or to high levels in some subtypes and low levels in others. Several central identified controls over subtype development, including Fezf2, Ctip2, Satb2, and Tbr1, interact combinatorially (although not linearly) as part of a broader molecular network and nested molecular logic that directs subtype identity acquisition.

Abbreviations A1, primary auditory cortex; Bhlhb5, basic helix-loop-helix domain-containing, class B5; Btg1, B cell translocation gene 1, antiproliferative; Cdh6, cadherin 6; Cdh8, cadherin 8; Cdh13, cadherin 13; Clim1, carboxyl-terminal LIM domain-binding protein 1; Couptf1, chicken ovalbumin upstream transcription factor I; CC, corpus callosum; CP, cortical plate; CPN, callosal projection neuron(s); CR, Cajal-Retzius cell(s); Crym, mu crystallin; CSMN, corticospinal motor neuron(s); Csmn1, zinc finger protein 703; CThPN, corticothalamic projection neuron(s); CTPN, corticotectal projection neuron(s); Ctip2, Couptf-interacting protein 2; Cux1, cut-like homeobox 1; Cux2, cut-like homeobox 2; Darpp32, dopamine- and cAMP-regulated neuronal phosphoprotein; Diap3, diaphanous homolog 3; Dkk3, dickkopf homolog 3; DL, deep layer (layers V and VI); dLG, dorsal lateral geniculate nucleus of thalamus; E, embryonic day; Emx2, empty spiracles homeobox 2; Epha7, Eph receptor A7; Fezf2, Fez family zinc finger 2;Fog2 , friend of GATA 2; FoxP2, forkhead box P2; GC, granule cell(s); Gfra2, glial cell-line-derived neurotrophic factor family receptor α 2; Hspb3, heat shock protein 3; Id2, inhibitor of DNA binding 2; Igfbp4, insulin-like growth factor binding protein 4; Inhba, inhibin β-A; IP, intermediate progenitor; Lhx2, LIM homeobox protein 2; Limch1, LIM and calponin homology domains 1; Lix1, limb expression homolog 1; Lmo4, LIM domain-only 4; Lpl, lipoprotein lipase; M1, primary motor cortex; MZ, marginal zone; NE, neuroepithelial cell; Nfib, nuclear factor IB; Ngn2, neurogenin 2; Odz3, odd Oz/ten-m homolog 3; oRG, outer radial glia; OT, optic tectum (superior colliculus); Otx1, orthodenticle homolog 1; P, postnatal day; Pax6, paired box gene 6; Plxnd1, plexin D1; PP, preplate; RG, radial glia; Rorb, RAR-related orphan receptor beta; S1, primary sensory cortex; S100a10, S100 calcium-binding protein A10; Satb2, special AT-rich sequence binding protein 2; SC, spinal cord; SCPN, subcerebral projection neuron(s); Sox5, SRY box-containing gene 5; Sox6, SRY box-containing gene 6; SP, subplate neuron(s); Sp8, trans-acting transcription factor 8; SVZ, subventricular zone; Tbr1, T box brain gene 1; Tbr2, T box brain gene 2; Tcrb, T cell receptor β chain; Tle4, transducin-like enhancer of split 4; UL, upper layer (layers II/III and IV); V1, primary visual cortex; VL, ventral lateral nucleus of thalamus; VP, ventral posterior nucleus of thalamus; VZ, ventricular zone; WM, white matter.

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918.e1 Cell 151, November 9, 2012 ©2012 Elsevier Inc. DOI http://dx.doi.org/ 10.1016/j.cell.2012.10.004