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Transcriptional Regulation of Neuronal Polarity and Morphogenesis in the Mammalian Brain

Luis de la Torre-Ubieta1 and Azad Bonni1,* 1Department of Neurobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2011.09.018

The highly specialized morphology of a neuron, typically consisting of a long axon and multiple branching dendrites, lies at the core of the principle of dynamic polarization, whereby information flows from dendrites toward the soma and to the axon. For more than a century, neuroscientists have been fascinated by how shape is important for neuronal function and how neurons acquire their characteristic morphology. During the past decade, substantial progress has been made in our understanding of the molecular underpinnings of neuronal polarity and morphogenesis. In these studies, transcription factors have emerged as key players governing multiple aspects of neuronal morphogenesis from neuronal polarization and migration to axon growth and pathfinding to dendrite growth and branching to synaptogenesis. In this review, we will highlight the role of transcription factors in shaping neuronal morphology with emphasis on recent literature in mammalian systems.

Introduction: The Life of a Neuron Is a Transcriptional mentally inherited pathways that operate largely independently Smorgasbord of cellular environments, orchestrate neuronal responses to To integrate into neuronal circuits, newly generated neurons extrinsic cues and in turn may be influenced by these cues. engage in a series of stereotypical developmental events. After Invertebrate model organisms have been invaluable to the study exit from the cell-cycle, postmitotic neurons first undergo axo- of the cell-intrinsic mechanisms that orchestrate neuronal dendritic polarization, a process that encompasses the initial morphogenesis. Elegant studies in Drosophila have spear- specification of axons and dendrites and their coordinate growth headed the discovery of in vivo functions for transcription factors giving rise to the unique neuronal shape. Concurrently, many in diverse aspects of neuronal morphogenesis. In particular, neurons undergo extensive migration to reach their final destina- studies of the da sensory neurons in the fly peripheral nervous tions in the brain. Axons grow to their appropriate targets, system have defined roles for different transcription factors in dendrites arborize and prune to cover the demands of their distinct aspects of dendrite development, from growth and receptive field, and synapses form and are refined to ensure branching to tiling (Jan and Jan, 2003, 2010). proper connectivity. How neurons accomplish all these tasks Several observations also highlight the importance of cell- has been the subject of intense scrutiny during the past few intrinsic mechanisms in the control of neuronal morphogenesis decades. A large body of work has established that these funda- and connectivity in mammalian neurons. For example, the in vivo mental developmental events are regulated by extrinsic cues developmental programs of polarization, migration, axon and including secreted polypeptide growth factors, adhesion mole- dendrite growth, and synapse formation are recapitulated in cules, extracellular matrix components, and neuronal activity distinct populations of neurons dissociated in primary culture (Dijkhuizen and Ghosh, 2005b; Huber et al., 2003; Katz and (Banker and Goslin, 1991; Powell et al., 1997). Of course, Shatz, 1996; Markus et al., 2002a; McAllister, 2002; Tessier-Lav- extrinsic cues and cell-intrinsic mechanisms do not operate in igne and Goodman, 1996). Extrinsic cues are thought to regulate isolation. Isolated primary Purkinje neurons polarize and extend both the overall design of neuronal shape as well as their fine axons, but the proper formation of their dendrites and dendritic structural elements such as axon branch points and dendritic spines requires signals from granule neurons (Baptista et al., spines. Growth factors, guidance proteins, and other extrinsic 1994). Nevertheless, although extrinsic signals influence neu- cues act via specific cell surface receptor proteins, which in ronal morphogenesis, neurons often seem to carry a memory turn regulate intracellular signaling proteins that directly influ- or intrinsic potential that is not altered by a new and different ence cytoskeletal elements. Members of the Rho GTPase family environment. Transplantation studies have suggested that of proteins and protein kinases have emerged as key signaling neuronal precursors of the cerebral cortex that give rise to intermediaries that couple the effects of extrinsic cues to the later-born upper layer neurons are restricted in their develop- control of actin and microtubule dynamics (Dhavan and Tsai, mental potential and do not give rise to earlier-born deep-layer 2001; Dickson, 2002; Govek et al., 2005; Hur and Zhou, 2010; neurons when placed in the subventricular zone (SVZ) of younger Luo, 2000; O’Donnell et al., 2009; Wayman et al., 2008b). hosts undergoing deep layer neurogenesis (Desai and McCon- Accumulating evidence also supports the concept that cell- nell, 2000; Frantz and McConnell, 1996). Likewise, transplanta- intrinsic mechanisms have major roles in neuronal morphogen- tion studies have revealed that dendrite morphology and laminar esis and connectivity. These mechanisms comprise develop- specificity of granule neurons in the rat olfactory bulb appear to

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be specified at the time of birth in the SVZ (Kelsch et al., 2007). axons and then dendrites in vivo is closely reproduced when These studies are consistent with the idea that cell intrinsic mech- these cells are grown in primary culture or in organotypic cere- anisms specify a developmental template for different popula- bellar explants (Kawaji et al., 2004; Powell et al., 1997). These tions of neurons that is retained in new environments. This studies suggest that the basic set of instructions to shape intrinsic identity may also influence how neurons respond to granule neurons is intrinsically encoded. In light of the high abun- extrinsic cues. Application of the same neurotrophic factor to dance of granule neurons in the cerebellum, the existence of neurons located in distinct cerebral cortical layers elicits differen- methods to obtain a highly homogeneous population of granule tial effects on dendrite morphology (McAllister et al., 1995, 1997), neurons from the rat or mouse brain (Bilimoria and Bonni, 2008), suggesting that neurons inherit distinct developmental programs a relatively simple circuit architecture and accessibility for in vivo that dictate their responses to extrinsic signals. Purified rat studies, the cerebellar cortex has become an excellent system to embryonic retinal ganglion neurons cultured in a variety of condi- study intrinsic determinants of neuronal morphogenesis. tions grow axons much faster than ganglion neurons from post- Transcription factors play critical roles in all major stages of natal animals (Goldberg et al., 2002b). In addition, with matura- the life of a granule neuron in the cerebellar cortex (Figure 1). tion retinal granule neurons undergo a switch from preferential These will be briefly described here and examined in depth in axon growth to preferential dendrite growth (Goldberg et al., subsequent dedicated sections. Axon growth in granule neurons 2002b). Collectively, these observations suggest that neurons is controlled by the transcriptional regulators SnoN and Id2, both harbor developmentally inherited cell-intrinsic mechanisms that of which are subject to degradation by the ubiquitin proteasome determine in large part neuronal morphogenesis. system (Konishi et al., 2004; Lasorella et al., 2006; Stegmu¨ ller Transcriptional control of gene expression represents a major et al., 2006). Cdh1-anaphase promoting complex (Cdh1-APC), mode of cell-intrinsic regulation of neuronal development. Tran- an E3 ubiquitin ligase, targets SnoN and Id2 for degradation scription factors can govern entire developmental programs, and in turn restricts axon growth (Konishi et al., 2004; Lasorella directing distinct stages of neuronal development as well as et al., 2006; Stegmu¨ ller et al., 2006). Interestingly, a recent study altering the competency and response of cells to extrinsic has revealed that SnoN also regulates in an isoform-specific cues. Accordingly, often the expression of one or a set of tran- manner granule neuron migration and positioning by controlling scription factors is sufficient to direct the subtype specification the expression of the microtubule-binding protein doublecortin of distinct neuronal populations and thus their morphology and (Dcx) (Huynh et al., 2011). projection patterns (Arlotta et al., 2005; Chen et al., 2005b; Following parallel fiber axon growth, establishment of synaptic Hand et al., 2005; Lai et al., 2008; Liodis et al., 2007; Molyneaux connections in the molecular layer occurs through complex et al., 2005, 2007; Polleux et al., 2007). The current challenge is interactions between pre-synaptic sites in parallel fiber axons to understand the extent of intrinsic regulation by identifying the and dendritic spines in Purkinje neurons. The development of transcription factors responsible in different aspects of neuronal parallel fiber presynaptic sites has recently been discovered to morphogenesis, their direct targets, and the interplay with be under the purview of transcription factor regulation as well, extrinsic cues. with the basic helix-loop-helix (bHLH) family member NeuroD2 Studies of the mammalian cerebellar cortex have highlighted inhibiting the formation of presynaptic sites in newly generated the importance of transcription factors in distinct aspects of granule neurons (Yang et al., 2009). Analogous to SnoN-and neuronal morphogenesis and connectivity (Figure 1). The rodent Id2-control of axon growth, NeuroD2 is also regulated by the cerebellar cortex provides an excellent model system for the ubiquitin-proteasome pathway where the Cdh1-APC-related study of mechanisms that shape neurons (Altman and Bayer, ligase Cdc20-APC triggers NeuroD2 degradation in mature 1997; Hatten, 1999; Palay and Chan-Palay, 1974; Ramo´ n y Cajal, neurons and thereby promotes presynaptic differentiation 1995). Postmitotic granule neurons are generated after division of (Yang et al., 2009). Thus, different aspects of axon development, progenitors located in the external granule layer (EGL). A newly growth and presynaptic development are regulated by the APC generated granule neuron first extends a single process along acting on different transcription factors. the molecular layer (ML). A second process is then generated Dendrite development in granule neurons consists of a series at the opposite pole of the neuron, giving it a bipolar morphology. of events beginning with the initiation of growth and branching, A phase of tangential migration follows as the bipolar processes leading to the formation of an exuberant arbor, followed by continue to grow before the neuron generates a third leading pruning, and culminating in the formation of postsynaptic struc- process perpendicular to the plane of the ML that directs somal tures termed dendritic claws at the ends of the remaining few migration radially toward the internal granule layer (IGL). As the dendrites. Dendritic claws house sites of connectivity with soma migrates inward in the cerebellar cortex, the two processes mossy fiber terminals and Golgi neuron axons (Altman and in the ML fuse while the neuron continues to extend a trailing Bayer, 1997; Palay and Chan-Palay, 1974; Ramo´ n y Cajal, process perpendicular to the plane of the ML. The intersection 1995). As with the axons, dendrite growth and maturation of these orthogonally oriented processes gives rise to the charac- are also under transcriptional control in granule neurons. Intrigu- teristic T-shaped parallel fiber axon of granule neurons. Once ingly, transcription factors in these developmental steps are granule neurons reach the IGL, they begin to extend dendrites, strongly influenced by neuronal activity and calcium signaling. which following pruning and maturation establish synaptic The bHLH transcription factor NeuroD promotes dendrite connections (Altman and Bayer, 1997; Ramo´ n y Cajal, 1995). growth in response to activation of L-type voltage sensitive The stereotyped sequence of events by which granule neu- calcium channels (VSCCs) (Gaudillie` re et al., 2004). In a later rons acquire a polarized morphology by sequentially generating phase of development, the sumoylated repressor form of the

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FOXO P1 Pak1

p300 EGL

SnoN1/2N1 2 Polarization Ccd1 Id2

E47 ML NogoR, Sema3F, Unc5A, Notch1, Jagged2 Axon growth Axon

Barhl1 NT-3

CREB IGL BDNF Developmental Time Developmental

NFIA,B,X EphrinB1, N-Cadherin

SnoN1 FOXO1

Dcx Migration and Positioning Dendritic claw formation Dendrite pruning P8 Dendrite growth Presynapticres naptic site formation ormation Developmental Time P12 NrNeuroD Cdc20 - ? APC NeuroD2r Cplx2

Rat cerebellum Sp4 NT-3

SUMO MEF2A Nur-77

Figure 1. Transcription Factors Orchestrate Distinct Stages of Neuronal Morphogenesis in the Cerebellar Cortex The morphogenesis of granule neurons in the cerebellar cortex proceeds in discreet stages governed by distinct transcription factors. After exit from the cell cycle, the FOXO transcription factors trigger granule neuron polarization by regulating the expression of the kinase Pak1. Axon growth is promoted by at least two transcriptional regulators, SnoN1 and SnoN2, acting as transcriptional coactivators in association with p300, and the bHLH inhibitor protein Id2. The tran- scriptional regulator SnoN2 promotes migration from the IGL into the EGL by inhibiting the transcriptional repressor complex SnoN1/FOXO1. The transcription factors Barhl1, NFIA, B, X, and CREB also promote migration into the IGL. The SnoN1/FOXO1 transcriptional complex directly represses Dcx and thereby controls the positioning of granule neurons within the IGL. Dendrite morphogenesis includes the stages of growth, pruning and maturation. The transcription factor NeuroD promotes the initiation of dendrite growth and branching, while Sp4 regulates dendrite pruning, and the sumoylated repressor form of the transcription factor MEF2A drives the differentiation of postsynaptic dendritic claws. Concurrent with dendrite pruning and maturation, development of presynaptic structures in parallel fiber axons is regulated by the transcription factor NeuroD2, which is regulated by the ubiquitin ligase Cdc20-APC. Image depicts a coronal or parlobular section of the rat cerebellar cortex at different stages of development as drawn by Ramo´ n y Cajal (1995). See text for details. transcription factor myocyte enhancer factor 2A (MEF2A) drives orchestrating programs of gene expression to shape axons postsynaptic dendritic claw differentiation in a manner that is and dendrites and ultimately synapses with other neurons. also regulated by VSCC activation (Shalizi et al., 2006). These studies suggest that activity-dependent calcium signaling regu- FOXO Transcription Factors Regulate Neuronal lates dendrite growth and maturation at least in part through Polarization and Positioning changes in gene expression governed by transcription factors. The polarization of neurons leading to the generation of axons The rather ubiquitous presence of transcription factor regula- and dendrites represents an essential step in the establishment tion in different aspects of neuronal morphogenesis has been of neuronal circuits in the developing brain. Mature axons and extended to the earliest step of neuronal polarization. Accord- dendrites are morphologically, biochemically, and functionally ingly, the FOXO transcription factors (Forkhead domain type O) distinct (Craig and Banker, 1994; Falnikar and Baas, 2009). have been discovered to trigger neuronal polarization in the Understanding the mechanisms by which neurons acquire and mammalian brain (de la Torre-Ubieta et al., 2010). Thus, as maintain a polarized morphology is a fundamental question in soon as neurons are born, transcription factors go to work neurobiology.

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The study of the molecular basis of neuronal polarization is a postnatal rat pups. FOXO knockdown triggers the formation of relatively recent endeavor. Within this growing field, the majority aberrant processes in the IGL and the loss of associated parallel of the molecular players regulating neuronal polarity have been fiber axons (de la Torre-Ubieta et al., 2010). Expression of an characterized in studies of primary hippocampal neurons (Dotti RNAi-resistant form of FOXO6 in the background of FOXO et al., 1988). After plating, dissociated hippocampal neurons first RNAi reverses the polarity phenotype in primary neurons and issue several undifferentiated neurites (stage 2). Afterwards, one in postnatal rat pups. These findings suggest that the FOXO tran- of the neurites is selected by an apparent stochastic process to scription factors, and in particular the brain-enriched protein become an axon, displaying accelerated growth with concomi- FOXO6, play a critical role in the regulation of neuronal polarity. tant expression of axon markers (stage 3) (Craig and Banker, How might transcription factors drive neuronal polarization, an 1994). Axon specification, which occurs during the transition event that is specified locally within neuronal processes? A plau- from stage 2 to stage 3, represents a critical step in neuronal sible model would be that they trigger the expression of polarity- polarization. An array of proteins including molecular scaffolds, associated proteins and thereby establish the competency of Rho-GTPases and their regulators, protein kinases, kinesin neurons to undergo polarization. Consistent with this model, motors, and microtubule-associated proteins (MAPs) converge analysis of an array of genes implicated in neuronal polarity at the nascent axon to regulate cytoskeletal dynamics and suggests that the FOXO transcription factors regulate the promote axon specification and growth (Arimura and Kaibuchi, expression of the polarity complex protein mPar6, the Ras- 2007; Barnes and Polleux, 2009). Other studies using the cerebral GTPase R-Ras, the Rac1-GEF STEF, the MAPs adenomatous cortex as a model system are beginning to implicate extracellular polyposis coli (APC) and collapsing response mediator protein signals in axon formation. The neurotrophin BDNF and the growth 2 (CRMP-2), the kinesin family member KIF5A, and the protein factor TGF-b act via the protein kinases SAD-A/B and the Par kinase Pak1 (Figure 2; de la Torre-Ubieta et al., 2010). Within complex, respectively, to promote axonogenesis (Barnes et al., this set of genes, Pak1 is the most robustly downregulated 2007; Shelly et al., 2007; Yi et al., 2010). Extrinsic cues may also gene in FOXO-knockdown neurons. The FOXO proteins occupy regulate neuronal polarization by preventing axon differentiation the Pak1 gene and thereby directly activate Pak1 transcription in favor of dendrite morphogenesis. The guidance cue Sema- in neurons. Knockdown of Pak1 in granule neurons phenocopies phorin 3A (Sema 3A) repels axons and attracts apical dendrites the polarity phenotype induced by FOXO knockdown, and ex- in cortical neurons (Polleux et al., 2000). Two recent studies pression of Pak1 partly reverses the polarity phenotype triggered have expanded upon these findings, suggesting that Sema 3A by FOXO RNAi (de la Torre-Ubieta et al., 2010). These findings signaling in diverse populations of neurons suppresses axon suggest that the protein kinase Pak1 is a direct and physiologi- specification and instead promotes dendrite formation (Nish- cally relevant transcriptional target of the FOXO proteins in the iyama et al., 2011; Shelly et al., 2011). Sema 3A suppresses control of neuronal polarity, though additional targets mediating axon differentiation by inducing cGMP/PKG signaling and FOXO-dependent neuronal polarity remain to be identified. concomitantly reducing cAMP levels and inhibiting PKA activity, Pak1 activity is regulated by the Rho-GTPases Cdc42 and thus leading to decreased activity of the axon-promoting kinases Rac1 (Bokoch, 2003), which interact with the Par polarity LKB1 and SAD-A/B and increased activity of GSK3b (Shelly et al., complex (Joberty et al., 2000; Lin et al., 2000), suggesting that 2011). However, Sema 3A knockout as well as BDNF knockout Pak1 may be activated locally at the nascent axon downstream mice do not display overt defects of neuronal polarity, suggesting of the Par complex. Thus, the FOXO transcription factors may that alternative compensatory mechanisms are at play (Behar control both the expression of Pak1 and its upstream regulators et al., 1996; Ernfors et al., 1994; Jones et al., 1994; Polleux (Figure 2). The FOXO proteins regulate the expression of the et al., 1998, 2000). Other studies suggest that the plane of the microtubule-associated protein APC (de la Torre-Ubieta et al., last mitotic division and the position of the centrosome provide 2010), which localizes mPar3 to the nascent axon (Shi et al., spatial cues that establish the site of axon generation in both 2004), and expression of the kinesin KIF5A, which is important primary hippocampal and cortical neurons in vivo (de Anda for the transport of CRMP-2 to the axon (Kimura et al., 2005). et al., 2005, 2010). Although these studies have begun to elucidate Therefore, the FOXO transcription factors may act as critical the local mechanisms responsible for axon specification and regulators of polarity by triggering the expression of several polarization, the cell-intrinsic regulatory mechanisms that might components of the local machinery controlling neuronal polarity. orchestrate neuronal polarization have been largely unexplored. The discovery of FOXO proteins as key determinants of polarity Recently, the FOXO transcription factors have been identified should pave the way for future studies aimed at identifying addi- as key regulators of neuronal polarity (Figure 2). The FOXO pro- tional potential transcriptional regulators in neuronal polarity. teins are expressed in developing neurons in the brain, including The FOXO transcription factors are tightly controlled by post- in hippocampal and cerebellar granule neurons at a time when translational modifications, raising the question of how their they undergo neuronal polarization and morphogenesis. Knock- function in neuronal polarity might be regulated. Growth factors down of FOXO1, FOXO3, and FOXO6 by RNA interference inhibit FOXO-dependent transcription via the PI3K-Akt signaling (RNAi) in primary granule or hippocampal neurons leads to pathway (Biggs et al., 1999; Brunet et al., 1999; Gan et al., 2005; profound impairment of neuronal polarity (de la Torre-Ubieta Guo et al., 1999; Kops et al., 1999; Nakae et al., 2000; Zheng et al., 2010). FOXO knockdown neurons extend several unspec- et al., 2002). Interestingly, IGF-1 signaling and localized PI3K ified, morphologically similar processes that express both activity at the nascent axon promote axon specification in hippo- axonal and dendritic markers. This phenotype is recapitulated campal neurons (Jiang et al., 2005; Me´ nager et al., 2004; Shi in the cerebellar cortex in vivo upon induction of FOXO RNAi in et al., 2003; Sosa et al., 2006; Yoshimura et al., 2006), raising

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FOXO Pak1

Par6 APC CRMP-2 Kif5A

aPKC Par6 APC Par3Pr

Regulation of Actin and Microtubule Dynamics Kif5A

CRMP-2

Pak1

Figure 2. FOXO Transcription Factors Drive Neuronal Polarization FOXO transcription factors occupy the Pak1 gene promoter and induce its expression to promote neuronal polarization. The kinase Pak1 regulates actin and microtubules dynamics by distinct mechanisms at the nascent axon and is required for neuronal polarization. A number of additional FOXO putative tran- scriptional targets, including mPar6, APC, Kif5A, and CRMP-2 regulate polarization by acting locally at the nascent axon. The Par complex protein mPar3 is targeted to the nascent axon by APC. The microtubule-associated protein CRMP-2 is transported to the axon by Kif5A. a potential paradox of how the FOXO transcription factors, which suppressors in hematopoietic stem cells in vivo (Paik et al., are inhibited by the PI3K-Akt signaling pathway, promote 2007; Tothova et al., 2007). However, genetic ablation of different neuronal polarization. It remains unclear, however, whether FOXO family members in mice results in distinct phenotypes localized Akt signaling in the axon influences the activity of the in vivo (Castrillon et al., 2003; Furuyama et al., 2004; Hosaka FOXO transcription factors in the nucleus. Notably, growth factor et al., 2004; Kitamura et al., 2002; Lin et al., 2004; Nakae et al., inhibition of FOXO proteins can be countered in cellular contexts 2002; Polter et al., 2009; Renault et al., 2009), suggesting specific whereby the protein kinases MST1, JNK, and AMPK promote the roles for individual family members. The FOXO proteins FOXO1, nuclear accumulation of FOXO proteins and thereby induce FOXO3, and FOXO6 appear to operate redundantly in driving FOXO-dependent transcription (Essers et al., 2004; Greer neuronal polarization (de la Torre-Ubieta et al., 2010). However, et al., 2007; Lehtinen et al., 2006). It will be interesting to in rescue experiments in the background of FOXO RNAi, expres- determine if these or other signals stimulate FOXO-dependent sion of FOXO1 or FOXO3 only partially restores polarity, whereas transcription in neuronal polarization. expression of FOXO6 substantially restores polarity. Therefore, There has been much interest in the specific biological roles FOXO6 may have some nonoverlapping functions in neuronal of different FOXO family members. The FOXO proteins are ex- polarity. It will be important in the future to characterize the tran- pressed in overlapping patterns in the brain and other tissues scriptional targets of individual FOXO family members to under- and appear to bind to similar sites within responsive genes stand the contribution of each FOXO protein to neuronal polarity. (Furuyama et al., 2000; Hoekman et al., 2006). Accordingly, the Neuronal polarization temporally overlaps with radial migration FOXO transcription factors have redundant roles as tumor in certain populations of neurons in the mammalian brain. In the

26 Neuron 72, October 6, 2011 ª2011 Elsevier Inc. Neuron Review

A Figure 3. Isoform-Specific Functions of SnoN in the Control of Migration and Axon Growth Nucleus Sno EGL (A) The two spliced isoforms of the gene, SnoN1 and SnoN2, have distinct roles in granule neuron migration. SnoN2

SnoN2 promotes migration from the EGL into the IGL, while SnoN1 regulates positioning within the IGL. SnoN1 associates with SnoN2 the transcription factor FOXO1 and thereby represses Dcx Regulation of migration gene expression. SnoN2 inhibits SnoN1 function. from EGL to IGL and positioning (B) SnoN associates with the transcriptional coactivator p300 and promotes axon growth by inducing the expression of SnoN1 in the IGL FOXO1 Ccd1. Extrinsic cues impinge on SnoN function during Dcx SnoN1 development. TGF-b induces Smad2 phosphorylation and thereby stimulates Cdh1-APC-dependent degradation of IGL SnoN and consequent inhibition of axon growth.

β TGF- SnoN1 and SnoN2, which differ by a 46 amino acid B region present only in SnoN1 (Pearson-White and Cytoplasm Crittenden, 1997; Pelzer et al., 1996). SnoN1 has P an essential function in limiting the extent of migra- Smad2 tion of granule neurons within the IGL and thus in Nucleus the correct positioning of granule neurons within the IGL. Specific knockdown of SnoN1 in granule p300 neurons in vivo results in abnormal accumulation SnoN1/22 of granule neurons within the deep IGL close to Ccd1 Axon growth the white matter (Huynh et al., 2011). By contrast,

P SnoN2 promotes the migration of granule neurons

Cdh11 - Smad2 from the EGL to the IGL. Accordingly, SnoN2 APC knockdown impairs migration into the IGL, leading SnoN1/2 Inhibition of axon growth Ccd1 to the accumulation of granule neurons in the EGL (Huynh et al., 2011). Therefore, SnoN1 and SnoN2 have opposing functions in the control of granule neuron migration (Figure 3). developing cerebral cortex, cortical neurons undergo a transition The SnoN isoforms control migration in part by regulating the from a multipolar to bipolar morphology as they leave the inter- expression of the X-linked mental retardation and epilepsy gene mediate zone (IZ) and move toward the cortical plate, and this encoding doublecortin (Dcx). Dcx promotes microtubule stability morphological transition is regarded as polarization in cortical and polymerization and is thought to be critical for the dynamic neurons (Calderon de Anda et al., 2008; Noctor et al., 2004; coupling between the nucleus and the centrosome during nucle- Tabata and Nakajima, 2003). Interestingly, genes implicated in okinesis (Gleeson et al., 1999; Horesh et al., 1999; Koizumi et al., axo-dendritic polarization including the mPar complex protein 2006). SnoN1 forms a transcriptional complex with FOXO1 that Par6, the kinases LKB1, MARK2, GSK3b, and Pak1, and the occupies the Dcx gene and thereby represses its expression in Rho GTPases Rac1 and Cdc42 are also required for migration neurons (Figure 3; Huynh et al., 2011). Consistent with these find- (Asada and Sanada, 2010; Asada et al., 2007; Barnes and ings, knockdown of the SnoN1-FOXO1 complex derepresses Polleux, 2009; Causeret et al., 2009; Konno et al., 2005; Sapir Dcx expression and hence stimulates excessive migration of et al., 2008; Solecki et al., 2004). The migration phenotypes granule neurons within the IGL in the cerebellar cortex (Huynh associated with misregulation or inhibition of these genes often et al., 2011). SnoN2 antagonizes SnoN1 function by associating coincide with a multipolar or aberrant morphology in the stalled with SnoN1 via a coiled-coil domain interaction and inhibiting neurons. In view of these observations, in some instances it is the ability of SnoN1 to repress FOXO1-dependent transcription challenging to determine whether the failure of neurons to (Figure 3; Huynh et al., 2011). Thus, these findings both define polarize precedes the migration defects, or whether the inverse a transcriptional repressor complex for FOXO proteins and relationship holds. Notably, postmitotic granule neurons of the illustrate how control of abundance of two splicing isoforms of cerebellum undergo axo-dendritic polarization before the onset the same transcriptional regulator leads to opposing cellular of radial migration. In this sense, cerebellar granule neurons responses during development. provide a simpler system for the study of signaling pathways The study of neuronal polarization is relevant beyond the con- specific for migration or polarity. text of brain development. Spinal cord injury presents a scenario Taking advantage of this experimental system, a recent study where neurons have to regrow axons from an axonal stump. has uncovered that FOXO1 and the transcriptional regulator Axon transection can lead to the respecification of a dendrite SnoN play key roles in the migration and positioning of granule into an axon (Bradke and Dotti, 2000; Gomis-Ru¨ th et al., 2008; neurons in the cerebellar cortex (Figure 3; Huynh et al., 2011). Goslin and Banker, 1989; Takahashi et al., 2007). In particular, Alternative splicing generates two isoforms of the SnoN protein, depending on the proximity of the injury to the soma, neurons

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either extend an axon from the original stump or from a dendrite findings suggest that cell-intrinsic mechanisms orchestrate (Gomis-Ru¨ th et al., 2008). These studies suggest that neuronal responses to neurotrophins in the control of axon growth. polarity is plastic, and conversely the polarized state is actively Several lines of evidence support the concept that the maintained by dedicated mechanisms (Bisbal et al., 2008; capacity of a neuron to extend axons and project to the appro- Hedstrom et al., 2008; Jiang et al., 2005; Kobayashi et al., priate targets is intrinsically encoded. Neurons of the peripheral 1992; Nakada et al., 2003; Winckler et al., 1999; Yin et al., nervous system (PNS), but not the central nervous system (CNS), 2008). Thus, regulators of neuronal polarity might influence have the capacity to regenerate axons after injury (Aguayo et al., axon regeneration by directing axon re-specification and exten- 1991). The axon growth-inhibiting environment of the adult CNS, sion. In this regard, it will be important to determine if FOXO- chiefly generated by myelin proteins, contributes to this differen- dependent transcription is required for axon regeneration and tial response (Filbin, 2003; He and Koprivica, 2004; Schwab, in particular whether activators of FOXO proteins can accelerate 2004). However, the observation that embryonic CNS or adult axon growth after injury. Along these lines, increased SIRT1 PNS neurons can extend axons on top of adult white matter activity is associated with protection of dorsal root ganglion suggests that an intrinsic property of neurons in the adult CNS (DRG) axons from Wallerian degeneration (Araki et al., 2004). contributes to the failure of axon regeneration after injury (Davies In light of the observation that SIRT1-induced deacetylation et al., 1997, 1999; Schwab and Bartholdi, 1996). Consistently, of FOXO proteins stimulates FOXO-dependent transcription embryonic RGCs have a higher capacity to extend axons than (Brunet et al., 2004; Daitoku et al., 2004), the FOXO proteins postnatal RGCs, and this change in the capacity of axon growth might mediate the protective effect of SIRT1 against axon requires new gene transcription (Moore et al., 2009). Importantly, degeneration. Because the FOXO proteins are regulated by emerging evidence suggests that the intrinsic axonal growth distinct signaling pathways in response to cellular stress, capacity is regulated by transcription factors, both during devel- including the protein kinase JNK which stimulates axon regener- opment and in the context of injury. ation after injury (Lindwall et al., 2004), the FOXO proteins are Evidence for a cell-intrinsic mechanism regulating axon growth ideally positioned to promote axon regeneration after injury. has also emerged from studies of granule neurons of the devel- oping cerebellar cortex. The ubiquitin ligase Cdh1-APC plays Transcription Factors Regulate Axon Growth a critical role in the control of axon growth and patterning in the and Guidance: From Development to Regeneration rodent cerebellar cortex (Konishi et al., 2004). Knockdown of Several classes of neurons, including projection neurons in the Cdh1 in primary granule neurons stimulates axon growth even cerebral cortex must extend axons over very long distances in the presence of the growth-inhibiting environment of myelin. in a stereotyped path to innervate specific targets. Beyond Localization of Cdh1 in the nucleus is required for Cdh1-APC- the fundamental question of how neurons accomplish this inhibition of axon growth (Stegmu¨ ller et al., 2006). As briefly monumental task during development, understanding the mech- described above, subsequent studies have identified the tran- anisms that promote axon growth may form the basis of treat- scriptional modulator SnoN and the HLH protein Id2 as ments aimed at recovery in the central nervous system following substrates of neuronal Cdh1-APC in the control of axon growth injury or disease. (Lasorella et al., 2006; Stegmu¨ ller et al., 2006, 2008). Expression The role of extrinsic cues, including neurotrophic factors, in of SnoN alone can overcome myelin-dependent growth inhibi- promoting axon elongation is compelling. Exposure of distinct tion, suggesting that SnoN drives a genetic program that pro- populations of primary neurons, including retinal ganglion cells, motes axon growth under different extrinsic stimuli (Stegmu¨ ller DRG neurons, and hippocampal neurons to NGF, BDNF, or NT-3 et al., 2006). Interestingly, in contrast to the opposing functions promotes axon growth robustly (Goldberg et al., 2002a; Lentz of SnoN1 and SnoN2 in the control of granule neuron migration et al., 1999; Markus et al., 2002b; Shinoda et al., 2007). Impor- and positioning, the two isoforms of SnoN collaborate to promote tantly, a requirement for neurotrophin signaling in normal axon axon growth (Huynh et al., 2011; Stegmu¨ ller et al., 2006). Although development has been validated in vivo (Glebova and Ginty, SnoN is widely considered to have transcriptional repressive 2004; Kuruvilla et al., 2004; Patel et al., 2000, 2003; Tucker functions (Luo, 2004), including in the control of neuronal posi- et al., 2001). Neurotrophins act through the distinct Trk receptors tioning (Huynh et al., 2011), SnoN functions as a transcriptional activating signaling cascades relayed by the PI3K-Akt and coactivator in the control of axon growth (Figure 3; Ikeuchi Ras-MAPK signaling pathways, which in turn directly regulate et al., 2009). In particular, SnoN associates with the histone cytoskeletal elements modulating actin and microtubule polymer- acetyltrasferase p300 and thereby induces the expression of ization at the growth cone (Huber et al., 2003; Zhou and Snider, a large set of genes in neurons (Ikeuchi et al., 2009). These find- 2006). However, neurotrophins also induce changes in transcrip- ings support the concept that SnoN acts in a dual transcriptional tion that are thought to play critical roles in axon growth (Segal and activating or repressive manner in a cell-or target-specific Greenberg, 1996). Accordingly, neurotrophin signaling regulates manner (Pot and Bonni, 2008; Pot et al., 2010). In promoting the transcription factors CREB and NFAT to stimulate axon axon growth, the cytoskeletal scaffold protein Ccd1 represents growth (Graef et al., 2003; Lonze et al., 2002). Conversely, tran- a critical downstream target of SnoN (Ikeuchi et al., 2009). Ccd1 scription factors regulate the expression of neurotrophin recep- localizes to the actin cytoskeleton at growth cones and activates tors to specify neuronal subtypes and promote axon growth. the protein kinase c-Jun kinase (JNK) (Ikeuchi et al., 2009), which For example, the transcription factor Runx1 induces the timely has been implicated in axon growth (Oliva et al., 2006). expression of TrkA to promote the specification of nociceptive Whereas SnoN drives axon growth by triggering the expres- neurons and growth of their axons (Marmige` re et al., 2006). These sion of regulators of the actin cytoskeleton, Id2 is thought to

28 Neuron 72, October 6, 2011 ª2011 Elsevier Inc. Neuron Review

promote axon growth by antagonizing the function of the bHLH expression pattern of a number of KLF proteins from embryonic transcription factor E47, which induces the expression of a to postnatal stages correlates with their ability to suppress or number of genes involved in axon repulsion including NogoR, promote axon growth. Overexpression of KLF4, which is upregu- Sema3F, and Unc5A (Lasorella et al., 2006). Thus, Id2 stimulates lated postnatally in retinal ganglion neurons, suppresses axon axon growth by modulating the response of neurons to guidance growth. Conversely, retinal ganglion neurons from KLF4 knock- cues. Interestingly, TGFb signaling through the protein Smad2 out mice exhibit increased axon growth in culture and regenerate regulates the abundance of SnoN protein and consequently after optic nerve crush injury (Moore et al., 2009). These findings axon growth (Stegmu¨ ller et al., 2008), thus highlighting how support the idea that the regulated expression of transcription intrinsic determinants integrate signals from extrinsic cues for factors during development controls the intrinsic potential for proper development. axon growth in neurons. Although transcriptional regulators such as NFAT, SnoN, and Studies of axon regeneration in dorsal root ganglion (DRG) Id2 appear to regulate axon growth in postmitotic neurons, tran- neurons have also supported an important role for transcription scription factors that primarily regulate neurogenesis may also factors in the control of axon growth. Transection of the periph- coordinate axon growth in differentiated neurons. In studies of eral branch, but not the central branch, in DRG neurons triggers retinotectal projection neurons and spinal cord motor neurons, axon growth and promotes axon regeneration of central several transcription factors including Vax2, Zic2, Lim1, and branches following a later spinal cord injury (Neumann and Lmx1b have been reported to regulate the timely and cell- Woolf, 1999; Richardson and Issa, 1984; Smith and Skene, specific expression of proteins involved in axon guidance, 1997). Comparing the transcriptional profiles of DRG neurons including Ephrins A and B and their receptors (Barbieri et al., with transected central versus peripheral branches reveals that 2002; Dufour et al., 2003; Herrera et al., 2003; Kania and Jessell, approximately 10% of the genes with altered expression 12 hr 2003; Kania et al., 2000; Mui et al., 2002; Schulte et al., 1999; after the procedure are transcription factors (Zou et al., 2009). Williams et al., 2003). Neurons residing in distinct cerebral The transcriptional regulator Smad1 represents one of the genes cortical layers display specific projection patterns, suggesting upregulated in DRGs with transected peripheral branches rela- that subtype specification is linked to aspects of axon morpho- tive to central branches. Smad1 promotes axon growth in DRG genesis. Functional characterization of transcription factors neurons following injury, an effect that is potentiated by BMP exhibiting layer-specific expression in the cerebral cortex of signaling. Similar studies have identified a role for the transcrip- knockout mice has uncovered a requirement for the transcrip- tion factors STAT3, ATF3, CREB, and c-Jun in promoting axon tion factors FEZL and CTIP2 in the generation of proper layer growth after injury (Gao et al., 2004; Lindwall et al., 2004; Qiu V neuron projections to subcortical targets (Chen et al., 2005a; et al., 2005; Raivich et al., 2004; Seijffers et al., 2007; Tsujino Molyneaux et al., 2005). The transcription factors Tbr1 and et al., 2000). Changes in the expression of transcription factors Sox5 are required for the specification of layer VI neurons and have also been identified in other models of neuronal injury, their projections to the thalamus (Bedogni et al., 2010; Lai including stroke. A number of these transcription factors, et al., 2008; McKenna et al., 2011), and Sat2b is required for including STAT3 and KLF7 may play a role in axon sprouting after callosal projections (Alcamo et al., 2008; Britanova et al., stroke (Li et al., 2010b). Thus, there might be shared transcrip- 2008). Expression of Fezl or Ctip2 in vivo forces neurons to tional responses following stroke with those promoting axon acquire a deep-layer projection pattern while suppressing the regeneration after neuronal injury. Taken together, these studies expression of Tbr1 and Sat2b (Chen et al., 2008; Molyneaux highlight the importance of transcriptional responses in axon et al., 2005). Conversely, Tbr1 and Sat2b are thought to directly regeneration and offer the prospect that cell-intrinsic responses repress Fezl and Ctip2, respectively (Alcamo et al., 2008; might provide a target for development of new therapeutic possi- McKenna et al., 2011). Thus, a complex transcriptional network bilities in neurological diseases. specifies a particular cortical subtype, in part by suppressing the A major focus in the study of the role of transcription factors in expression of factors that drive alternate subtypes. Identification axon growth and regeneration is the identity of the relevant target of the downstream mechanisms mediating the effects of these genes. Axon guidance molecules including members of the transcription factors on cortical projection patterns will reveal ephrin and semaphorin families of proteins have been identified whether they are directly linked to the machinery controlling as key targets (Polleux et al., 2007). Fewer studies have identified axon growth and guidance or if they act primarily in neuron direct cytoskeletal regulators that might act at the growth cone specification. or in axon protein transport. The transcription factor COUP-TFI Considering the evidence indicating that neurons have a devel- (NR2F1) plays a critical role in neurogenesis, differentiation, opmentally regulated intrinsic axon growth capacity (Blackmore migration, and formation of commissural projections. Primary and Letourneau, 2006; Bouslama-Oueghlani et al., 2003; Gold- hippocampal neurons from COUP-TFI knockout mice initially berg et al., 2002b), several groups have sought to characterize grow short abnormal axons but later grow to the same extent the transcriptome of neurons exhibiting different axon growth as wild-type cells (Armentano et al., 2006). The expression of capabilities in development and in the context of injury (Costigan the cytoskeletal regulators MAP1B and RND2 is altered in et al., 2002; Me´ chaly et al., 2006; Moore et al., 2009; Zou et al., COUP-TFI knockout brains in microarray analyses (Armentano 2009). Transcriptional profiling of retinal ganglion neurons from et al., 2006). The tumor suppressor p53 has also been reported embryonic to postnatal stages has revealed that several mem- to promote axon growth by regulating the expression of cGKI, bers of the Krupel-like family (KLF) of transcription factors are a kinase that counteracts growth cone collapse induced by regulated throughout development (Moore et al., 2009). The semaphorin 3A signaling (Tedeschi et al., 2009b) or by inducing

Neuron 72, October 6, 2011 ª2011 Elsevier Inc. 29 Neuron Review

the expression of cytoskeletal regulators including GAP-43, phases. Just as with axon specification and neuron migration, Coronin1, and the GTPase Rab13 following axonal injury (Di granule neurons of the rodent cerebellar cortex provide a robust Giovanni et al., 2006; Tedeschi et al., 2009a). The case of p53 model system for the study of dendrite development including is more complex as other studies suggest that p53 can promote their distinct stages of growth, pruning, and postsynaptic axon growth independently of transcription by inhibiting Rho maturation (Figure 1). In recent years, a number of transcription kinase (ROCK) at the axon (Qin et al., 2009, 2010). Collectively, factors have been discovered to regulate distinct stages of these studies support the idea that transcription factors can dendrite development in granule neurons. As part of the independently regulate two different aspects of axon develop- process of establishing neuronal polarity, the FOXO transcrip- ment, growth and guidance, by inducing different target genes tion factors, and in particular the brain-enriched protein according to the developmental requirements of the cell. FOXO6, inhibit the growth of dendrites while simultaneously Is axon growth regulated by epigenetic mechanisms? promoting the growth of axons (de la Torre-Ubieta et al., Compelling evidence on epigenetic mechanisms selectively 2010). Thus, even as neurons migrate and their axons grow, regulating axon growth in the mammalian brain is scarce. Epige- transcriptional mechanisms are at play to inhibit the formation netic regulators including the histone acetyltransferase CBP and of dendrites. In this capacity, the FOXO proteins may inhibit the chromatin modifier Sat2b influence cortical and motor a cell-intrinsic switch from axon to dendrite growth in the neuron projection patterns, but this is also linked to a role in brain. The bHLH protein NeuroD plays a critical role in the initi- neuronal subtype specification (Alcamo et al., 2008; Britanova ation of dendrite growth as well as the branching of granule et al., 2008; Lee et al., 2009). Loss of function of the methyl- neuron dendrite arbors in the cerebellar cortex (Gaudillie` re CpG-binding transcriptional repressor MeCP2 has been associ- et al., 2004). While NeuroD promotes the initiation of dendrite ated with several abnormalities in neuronal morphogenesis growth and elaboration, the zinc-finger transcription factor including disrupted axon projections (Belichenko et al., 2009; Sp4 promotes the pruning of the granule neuron dendrite arbor Degano et al., 2009). Axonal targeting defects observed in (Ramos et al., 2007, 2009), and the MADS domain transcription MeCP2 knockout mice are attributed to changes in the expres- factor MEF2A triggers the morphogenesis of the postsynaptic sion of the guidance factor Semaphorin3F, albeit in a non-cell- dendritic claws (Shalizi et al., 2006, 2007). Collectively, these autonomous fashion (Degano et al., 2009). Among the genes studies support the concept that different transcription factors identified in a screen for axonal sprouting after stroke is ATRX are dedicated to distinct aspects of dendrite development (a-thalassemia/mental retardation syndrome X-linked) (Li et al., (Figure 1). Whether and how these transcription factors might 2010b), a chromatin remodeling enzyme linked to mental retar- regulate each other in the control of dendrite morphogenesis dation that has also been implicated in dendrite development is an unanswered question. and neuronal survival (Be´ rube´ et al., 2005; Shioda et al., 2011). An interesting feature of the role of transcription factors in ATRX appears to be upregulated in sprouting neurons relative the regulation of dendrite development is that they are robustly to nonsprouting neurons. Knockdown of ATRX by RNAi reduces influenced by calcium signaling and consequently neuronal basal axon growth of cultured DRG neurons and prevents axonal activity (Figure 4). Membrane depolarization is critical for the sprouting after stroke in vivo (Li et al., 2010b). Interestingly, ATRX development of dendrite growth and branching, including in and MeCP2 can interact in vitro and in cells, and in MeCP2 granule neurons of the cerebellar cortex (Gaudillie` re et al., knockout cells ATRX fails to localize to heterochromatin, display- 2004; Okazawa et al., 2009). Calcium influx via L-type calcium ing instead a diffuse expression pattern (Nan et al., 2007). Thus, channels triggers the activation of the protein kinase CaMKIIa some of the neuronal defects observed in MeCP2 mutants might (Hudmon and Schulman, 2002; Wayman et al., 2008b). Once be due to abnormal ATRX activity. Future studies will be needed activated, CaMKIIa induces the phosphorylation of NeuroD at to understand the extent of epigenetic mechanisms in axon Serine 336 (Gaudillie` re et al., 2004). Structure-function analyses growth. of NeuroD in the background of NeuroD RNAi indicate that the CaMKIIa-induced phosphorylation of NeuroD, including at Transcription Factors Direct Distinct Stages of Dendrite Serine 336, is essential for the ability of NeuroD to mediate mem- Morphogenesis brane depolarization-dependent dendrite growth (Gaudillie` re As the receptive limbs of neurotransmission in the brain, et al., 2004). How the CaMKIIa-induced phosphorylation acti- dendrites have evolved to display immense variety of shape vates the transcriptional function of NeuroD remains to be and size. Dendrite architecture strongly influences the process- determined. Since depolarization-induced NeuroD-dependent ing of information (Spruston, 2008), suggesting that the morpho- transcription in transient reporter assays is not affected by muta- genesis of dendrite arbors directly impacts the flow of informa- tion of Serine 336 (Gaudillie` re et al., 2004), the possibility that tion across the brain. Although we will focus on the role of the CaMKIIa-induced phosphorylation triggers changes in transcription factors on dendrite morphology in mammalian NeuroD-recruitment of chromatin remodeling enzymes is an systems, significant contributions in this field have also come intriguing possibility that remains to be tested. The NeuroD from studies in the fly nervous system. We refer the reader to target genes that couple calcium signaling to the growth of excellent reviews on this topic (Corty et al., 2009; Jan and Jan, dendrites also remain unknown. Interestingly, the role of NeuroD 2003, 2010). in dendrite morphogenesis seems to extend beyond early post- Dendrites come in greater variety of shapes and size than natal development into the regulation of dendrites in adult-born axons, and the morphogenesis of dendrites in different popula- neurons. Adult-born granule neurons of the hippocampus in tions of mammalian neurons proceeds in distinct stereotypical NeuroD null mice display shorter dendrites as compared to

30 Neuron 72, October 6, 2011 ª2011 Elsevier Inc. Neuron Review

Ca2+

VSCC or NMDAR

CaMKK Cytoplasm

Neuronal Activity CaMKIγ CaMKIV CaMKIIα ?

P P CREB NeuroD Nucleus

CREST

Other -BDNF TR -Wnt-2 -cpg15 BAF57 BRD7,9 BAF180 -Other genes regulating ARID1, BAF47 dendrite morphogenesis ARID2A,B BRG1,BRM BAF60A,C Actin P CBP P BAF45B,C BAF155 BAF170 BAF53B CREB NeuroD

Figure 4. Neuronal Activity Regulates Transcription-Dependent Dendrite Growth Activity-dependent gene expression is regulated at multiple levels. Neuronal activity leading to calcium influx via voltage-sensitive calcium channels or NMDA receptors leads to the activation of CaMKK and downstream kinases CaMKIg, CaMKIV, or CaMKIIa to regulate transcription factors that control dendrite growth. Activation of CaMKIg or CaMKIV leads to phosphorylation and activation of CREB, whereas CaMKIIa phosphorylates NeuroD and induces NeuroD-dependent transcription. A number of transcriptional regulators (TR) including CBP, CREST, TORC1, and CRTC1 associate and regulate CREB-dependent transcription. In another layer of regulation, epigenetic mechanisms, including chromatin modification by the chromatin remodeling complex nBAF have a critical role in activity- dependent dendrite growth. CREST associates with the nBAF complex and regulates the expression of a number of genes important for dendrite growth. The complex interplay between transcription factors, transcriptional regulators and chromatin modifying enzymes that regulate gene expression in response to neuronal activity remains to be elucidated. wild-type neurons (Gao et al., 2009). Whether calcium signaling MEF2A Lysine 408 from sumoylation to acetylation, thereby is relevant to NeuroD-dependent dendrite morphogenesis in converting MEF2A from a transcriptional repressor form to an adult-born neurons remains an open question. activator, and leading to the inhibition of postsynaptic dendritic Calcium signaling also regulates the function of the transcrip- claw differentiation (Shalizi et al., 2006). Consistent with these tion factor MEF2A in postsynaptic dendritic differentiation. A findings, activation of MEF2-dependent transcription triggers calcium-regulated sumoylated transcriptionally repressive form elimination of postsynaptic sites in other populations of brain of MEF2A drives the differentiation of dendritic claws in the cere- neurons (Barbosa et al., 2008; Flavell et al., 2006, 2008; Pfeiffer bellar cortex (Shalizi et al., 2006, 2007). Sumoylation of MEF2A et al., 2010; Pulipparacharuvil et al., 2008). What might be the at Lysine 408, which converts MEF2A into a transcriptional purpose of calcium influx through L-type VSCCs inhibiting the repressor, is dependent on the status of phosphorylation of a function of sumoylated MEF2A in postsynaptic dendritic claw nearby site, Serine 403, which in turn is regulated by the cal- differentiation? A plausible explanation is that calcium influx in cium-regulated phosphatase calcineurin (Shalizi et al., 2006). membrane depolarized granule neurons during earlier phases The phosphorylation of MEF2A at Serine 403 is required for the of dendrite development might coordinately promote dendrite sumoylation of MEF2A at Lysine 408, owing to increasing the growth and branching via NeuroD and concomitantly inhibit catalytic efficiency of the SUMO E2 enzyme Ubc9 acting on the premature formation of postsynaptic dendrite sites. Alterna- MEF2A as a substrate (Mohideen et al., 2009; Shalizi et al., tively, with neuronal maturation, calcium influx induced by trans- 2006). Strikingly, calcineurin-induced dephosphorylation of synaptic signaling might induce the refinement of postsynaptic MEF2A at Serine 403 triggers a switch in the modification of dendritic structures.

Neuron 72, October 6, 2011 ª2011 Elsevier Inc. 31 Neuron Review

The idea that calcium signaling and VSCCs induce the early Just as in the cerebellar cortex, studies of dendrite morpho- growth of dendrites and simultaneously inhibit the later steps genesis in the cerebral cortex and hippocampus have high- of dendrite development has been further evaluated in recent lighted the regulation of transcription factors by neuronal activity studies. Interestingly, the resting membrane potential of newly and calcium influx (Figure 4). Prominent among these is the generated granule neurons in the EGL is depolarized, and it is transcription factor cAMP-responsive element binding protein hyperpolarized with maturation in the IGL (Okazawa et al., (CREB), which is modulated by a variety of extrinsic cues and 2009). Hyperpolarization of granule neurons in cerebellar slices regulates neuronal survival, dendrite growth, and synaptic triggers dendritic pruning and differentiation, including the function (Flavell and Greenberg, 2008; Lonze and Ginty, 2002; formation of dendritic claws (Okazawa et al., 2009). Switching Shaywitz and Greenberg, 1999). Neuronal activity stimulates between these stages of dendrite morphogenesis coincides CaMKIV-dependent phosphorylation and activation of CREB in with changes in the expression of a large number of genes, cortical neurons and thereby induces dendrite growth and arbor- including the transcription factors Etv1, Math2, Tle1, and Hey1, ization (Redmond et al., 2002). In more recent studies, CaMKIg suggesting that these proteins might regulate dendrite matura- has been found to mediate neuronal activity-dependent phos- tion (Okazawa et al., 2009; Sato et al., 2005). Collectively, studies phorylation and activation of CREB in hippocampal neurons, of dendrite morphogenesis in the cerebellar cortex support the leading to increased dendritic arborization (Wayman et al., idea that both the early phases of dendrite growth and activity- 2006). The CREB coactivator CBP also participates in neuronal dependent remodeling are under the purview of transcription activity-induced dendrite morphogenesis (Redmond et al., factor regulation. 2002). Another calcium-regulated transcriptional coactivator Although studies in the cerebellar cortex have provided com- termed CREST, which also associates with CBP, is required pelling evidence for cell-intrinsic regulation of stage-dependent for activity-dependent dendrite growth development in the cere- dendrite morphogenesis that is widely relevant to diverse bral cortex (Aizawa et al., 2004). Recent studies have identified populations of neurons in the brain, transcription factors can additional CREB binding partners that act as coactivators also shape the development of dendritic arbors characteristic required for CREB-dependent dendrite growth, including of a particular neuronal subtype. Transcription factors set up TORC1 (transducer of regulated CREB activity) and CRTC1 complex dendrite morphologies in a neuron-specific manner (CREB-regulated transcription co-activator), which operate in Drosophila (Corty et al., 2009; Jan and Jan, 2003, 2010). Tran- downstream of activity-dependent signaling and BDNF, respec- scriptional mechanisms specifying dendrite arbors in the tively (Finsterwald et al., 2010; Li et al., 2009). These studies mammalian brain are also beginning to be described. Tempo- highlight the complexity of CREB-dependent transcription. It rally specific or layer-specific expression of transcription factors will be important to elucidate the context and signaling mecha- in the cerebral cortex may define the morphological identity nisms controlling the association of CREB with different coregu- of neurons (Arlotta et al., 2005; Molyneaux et al., 2009; Moly- lators and the consequences on CREB-dependent transcription. neaux et al., 2007). The zinc finger transcription factor Fezf2 is Although a role for these transcriptional regulators in dendrite required for dendritic arbor complexity in layer V/VI neurons development is compelling, the downstream mechanisms are specifically (Chen et al., 2005b). The mammalian homologs of incompletely understood. BDNF represents a potential relevant the Drosophila transcription factor Cut, Cux1 and Cux2, have target of CREB and associated proteins in the control of dendrite been implicated in layer II/III pyramidal neuron dendrite devel- development and branching (Cheung et al., 2007; Dijkhuizen and opment by two different groups, though with seemingly conflict- Ghosh, 2005a; Horch and Katz, 2002; McAllister et al., 1997; Tao ing conclusions (Cubelos et al., 2010; Li et al., 2010a). Using et al., 1998). The secreted signaling protein Wnt-2, which pro- a combination of knockout mice and in vivo RNAi to generate motes dendritic arborization, is also induced by CREB down- Cux1-and Cux2-deficient cortical neurons in the intact cerebral stream of neuronal activity (Wayman et al., 2006). Likewise, the cortex, Cubelos and colleagues have found that Cux1 and cpg15 gene, which encodes a GPI-anchored protein, is induced Cux2 additively promote dendrite growth and branching as by CREB downstream of calcium signaling and promotes well as dendritic spine formation. Cux1 and Cux2 directly repress dendrite arbor elaboration in Xenopus tectal neurons (Fujino the putative chromatin modifying proteins Xlr3b and Xlr4b, et al., 2003; Nedivi et al., 1998). Interestingly, the microRNA which couple Cux1 and Cux2 to regulation of dendritic spine miR-132 is also induced by CREB in an activity-dependent morphogenesis, while the transcriptional targets involved in manner and promotes the elaboration of dendrite arbors in dendrite arbor formation remain to be identified (Cubelos et al., hippocampal neurons (Magill et al., 2010; Wayman et al., 2010). In contrast, using cortical cultures Li and colleagues 2008a). Taking into account that CREB mediates several aspects have found that overexpression of Cux1, but not Cux2, de- of neuronal development including neuronal survival (Bonni creases dendrite complexity, and conversely that knockdown et al., 1999; Lonze et al., 2002; Riccio et al., 1999), identifying of Cux1 leads to excessive dendritic arbor size in cortical neu- the specific direct targets involved in dendrite growth will clarify rons. Li and colleagues have also reported that Cux1 directly the role of CREB in neuronal morphogenesis. represses the cell-cycle regulator p27kip1 and thereby inhibits The complexity of transcriptional regulation in activity-depen- dendrite growth through RhoA (Li et al., 2010a). The findings dent dendrite growth is further highlighted by evidence demon- from Cubelos and colleagues whereby Cux1 promotes dendritic strating that the nBAF chromatin remodeling complex is required complexity are consistent with the function of the fly homolog for dendrite development (Figure 4; Wu et al., 2007). The multi- Cut, suggesting functional evolutionary conservation of this tran- meric nBAF complex is assembled from several homologous scription factor. proteins in a developmental-specific manner. In the context of

32 Neuron 72, October 6, 2011 ª2011 Elsevier Inc. Neuron Review

this combinatorial assembly, the BAF53a subunit, which is tion. In addition, the functions of different transcription factors present in neuronal progenitors, is replaced by the BAF53b may overlap temporally to control a specific feature of neuronal subunit, which is specific for differentiated neurons (Lessard morphology and connectivity. et al., 2007). Genetic ablation of BAF53b in mice leads to An important goal of future research in the study of transcrip- abnormalities in basal and activity-dependent dendrite growth. tional regulation of neuronal morphogenesis will be to define the Interestingly, the nBAF complex associates with CREST and relationship between different transcription factors regulating modulates the expression of a large number of genes involved distinct phases of neuronal development. For example, it will in neurite growth (Wu et al., 2007). This is of particular interest be interesting to determine whether and how the functions of in light of the observation that at least two other epigenetic FOXO6, NeuroD, Sp4, and sumoylated MEF2A intersect in the regulators, the histone demethylase SMCX and the DNA course of orchestrating granule neuron dendrite arbor develop- methyl-binding transcriptional repressor MeCP2, which are ment in the cerebellar cortex. Do any of these transcriptional mutated in cases of X-linked mental retardation (XLMR) and factors regulate the expression of another factor acting in a Rett syndrome also control dendrite growth (Ballas et al., 2009; subsequent or preceding step of dendrite development? Do Iwase et al., 2007; Zhou et al., 2006). These studies suggest any of these factors interact with other transcription factors that epigenetic mechanisms altering chromatin structure, which and thereby regulate their activity? Finally, do upstream signals can drive longer lasting transcriptional changes or provide addi- impinging on a specific transcription factor, such as CaMKIIa tional levels of regulation, contribute to dendrite development. or calcineurin that control NeuroD and MEF2A activity respec- Elucidation of the interplay between these epigenetic regulators tively, influence the activity of another transcription factor acting and transcription factors in the context of dendrite development on a different stage of dendrite development? should advance our understanding of these disorders. Another important goal of future studies will be to determine The few transcription factors that have been characterized in the extent of programs of gene expression regulated by different dendrite development in the mammalian brain to date likely transcription factors acting at distinct stages of neuronal devel- only represent the tip of the iceberg. Further, the targets of opment. Advances in genomic technologies will facilitate these many of these transcription factors are largely unknown. Regula- studies and yield large datasets for analysis of transcription tors of cytoskeletal components, including Rho-GTPases and factor-dependent networks of genes at distinct developmental microtubule-binding proteins, have been identified as targets stages. Comparisons of these data sets as well as analyses of of transcription factor regulation in the context of dendrite devel- transcription factor occupancies at target genes should also opment (Cobos et al., 2007; Hand et al., 2005; Li et al., 2010a; Wu provide novel insights into cooperative mechanisms between et al., 2007). It will be interesting to determine whether additional different transcriptional regulators in neuronal morphogenesis mechanisms, including contact-mediated signaling and secre- and connectivity. Several transcription factors that direct tory function through the Golgi apparatus, also operate down- neuronal morphogenesis in postmitotic neurons also have roles stream of specific transcriptional regulators in the control of in neuron specification. Although dissociating such distinct dendrite morphogenesis. roles may not always be a simple task, transcriptional profiling coupled with ChIP-Seq analyses may allow for the characteriza- Concluding Remarks tion of targetomes associated with specific developmental Transcription factors play a prominent role in all facets of programs. neuronal development from neuronal polarization and migration The complexity of transcriptional regulation is vast. Transcrip- to axon and dendrite morphogenesis to synapse differentiation. tion factors are controlled by posttranslational modifications, A flurry of studies during the past decade has unraveled many which lead to changes in protein stability, localization, activity, functions of transcription factors and regulators in neuronal or interaction partners. These modifications may not simply development in the mammalian brain. Prior to these studies, stimulate or inhibit transcriptional activity of the factor but may transcription factors were generally considered to govern the induce a switch in the mode of a transcription factor’s function transition from precursor cells to postmitotic neurons, and this between activator and repressor. Additionally, association with transition was thought to unleash a differentiation program, re- epigenetic regulators, including chromatin remodeling com- sulting in the mature morphology of neurons. A major conclusion plexes, may induce longer lasting or widespread changes in of studies of the past decade is that transcription factors con- gene expression. Finally, transcription factors often regulate tinue to play key regulatory roles in postmitotic neurons to the expression of other transcription factors creating complex specify and regulate the development of distinct morphological cascades. How and to what extent these cascades may be compartments. Another related key conclusion is the concept involved in other aspects of neuronal morphogenesis is a task that different transcription factors are dedicated to distinct for future studies. phases of neuronal morphogenesis and connectivity. This, Finally, studies of transcriptional regulation offer the basis for however, is an oversimplification. Although some transcription elucidation of key mechanisms of brain development as well as factors have a restricted expression pattern and orchestrate serve the foundation for a better understanding of the molecular specific aspects of development, others operate in a pleiotropic basis of developmental disorders of the brain in which deregula- manner to regulate several steps of development. In some tion of neuronal morphogenesis and connectivity plays a promi- cases, transcription factors operate as nodes to coordinate nent role (Kaufmann and Moser, 2000; McManus and Golden, two different aspects of neuronal development, such as neuronal 2005; Penzes et al., 2011; Schwartzkroin and Walsh, 2000; Siso- branching and migration or dendrite growth and synapse forma- diya, 2004). Mutations in several transcriptional regulators have

Neuron 72, October 6, 2011 ª2011 Elsevier Inc. 33 Neuron Review

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