Neuronal subtype specification in establishing mammalian neocortical circuits.

Neuroscience Research 86 (2014) 37–49

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Neuroscience Research journal homepage: www.elsevier.com/locate/neures

Review article

Neuronal subtype specification in establishing mammalian neocortical circuits Takuma Kumamoto a , Carina Hanashima a,b,∗ a b

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 t i c l e

i n f o

Article history: Received 10 March 2014 Received in revised form 21 June 2014 Accepted 23 June 2014 Available online 11 July 2014 Keywords: Neocortex Cell fate specification Pallium Projection neuron Layer Evolution

a b s t r a c t The functional integrity of the neocortical circuit relies on the precise production of diverse neuron populations and their assembly during development. In recent years, extensive progress has been made in the understanding of the mechanisms that control differentiation of each neuronal type within the neocortex. In this review, we address how the elaborate neocortical cytoarchitecture is established from a simple 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 cerebrum to a mammalian-type neocortex, and extend these key findings in the light of mammalian evolution to understand how the neocortex in humans evolved from common ancestral mammals. © 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Contents 1. 2. 3. 4.

5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The classification of neocortical glutamatergic neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spatial origins of neocortical glutamatergic neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Temporal specification of neocortical glutamatergic subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Cell competence and lineage of neocortical subtypes – a question revisited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Genetic network underlying neocortical subtype segregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The mammalian-specific regulation of neocortical subtype specification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The evolvability of the neocortex – future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The neocortex is comprised of diverse arrays of neurons that are organized into laminar and columnar subdivisions and is the processing center for complex behaviors, including perceptions, voluntary movements and languages. This unique laminated brain system is observed throughout extant monotremes to humans (Haug, 1987; Meynert, 1868) and has proved to be highly

∗ Corresponding author at: Laboratory for Neocortical Development, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 6500047, Japan. Tel.: +81 78 306 3400; fax: +81 78 306 3401. E-mail address: [email protected] (C. Hanashima).

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compatible with increased size and number of functional areas during mammalian evolution (Rakic, 2009). Although its anatomical character has been long appreciated, the mechanisms underlying the specification and assembly of each neuronal component of the neocortex remain largely elusive. Despite common stem amniote origin, non-mammalian lineages develop highly disparate brain cytoarchitectures, such as a single-layered cortex in reptiles (Dugas-Ford et al., 2012; Nomura et al., 2013) and a nuclear organization in birds (Jarvis et al., 2013; Montiel and Molnar, 2013; Nomura et al., 2008; Suzuki et al., 2012). The acquisition of the laminated brain system is, therefore, one of the key events that enabled unique neural processing in mammals and may underlie high evolvability of the neocortex toward hominid evolution.

http://dx.doi.org/10.1016/j.neures.2014.07.002 0168-0102/© 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/3.0/).

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

In recent years, approaches from both developmental and evolutionary viewpoints have provided new insights into the molecular scenario underlying neocortical assembly and its function. The aim of this review is to decipher how the elaborate neocortical cytoarchitecture is uniquely established in mammals based on our updated knowledge on the mechanisms of specification of neuronal subtypes. We then examine these homologous cell components in non-mammalian vertebrates to address the key events that underlie the conversion of the cerebrum of stem amniotes to a mammalian-type neocortex. Finally, we extend these findings in the light of mammalian evolution, to address how the neocortex in humans may have evolved from ancestral mammals. 2. The classification of neocortical glutamatergic neurons Neocortical neurons can be classified into subtypes according to their connectivity, morphology, physiology and molecular properties. Of these, two major classes based on neurotransmitter expressions, glutamatergic projection neurons (approximately 80%) and GABA (␥-aminobutyric acid)-ergic interneurons (approximately 20%) create the sensory representation of the physical world. While interneurons connect in the vicinity to provide inhibition to the local circuit, projection neurons are excitatory and send axons to distant cortical and subcortical targets (Bartolini et al., 2013; Greig et al., 2013). Although these two populations intermix within the mature neocortex, they are generated from different sectors of the telencephalon. Interneurons are produced from the ventral eminences (Anderson et al., 1997), whereas projection neurons arise locally from the progenitors of the dorsal telencephalon (Gorski et al., 2002). In principle, the cytoarchitecture of the neocortex can be defined by its glutamatergic cell components. These excitatory neurons, which are arranged into horizontal layers, undergo further modifications that assemble them into tangentially organized columns and areas (Noctor et al., 2001; Rakic, 1988). Each column, typically responding to a specific sensory stimulus, such as a body part or sound representation, is considered a functional unit within the respective neocortical area. After Meynert (1868), Lewis (1878) and Hammarberg (1895), Brodmann was the first to unify the names of neocortical subtypes according to their laminar positions and morphologies. Ever since, layers I through VI are still used as common terminology in identifying the glutamatergic subtypes organized along the radial axis from superficial to deep. It is important to recognize that although laminar positions are indicative of their neuronal identity, the advent of molecular technology has brought forth its limitation in defining a specific subtype. For example, retrograde neuronal tracers combined with microarray analyses reveal further heterogeneity in cell populations even within the same layer (Arlotta et al., 2005; Molyneaux et al., 2009). Recent high-throughput transcriptome-profiling in rodents and primates has highlighted not only diverse expression patterns of protein-coding genes but also noncoding RNAs within and across neocortical layers (Belgard et al., 2011; Bernard et al., 2012; Fertuzinhos et al., 2014). Therefore, a given neuronal type can only be defined by supplemental criteria, including their molecular and hodological properties. Based on these, the classification of representative layer glutamatergic neurons currently falls into the following subtypes, which has been best delineated in mice. Layer I is a relatively cell sparse layer, which accommodates mainly intercellular synapses of axonal fibers and dendritic tufts of pyramidal neurons. However, it consists of a unique neuron population called Cajal–Retzius (CR) cells during development. Although approximately 75% of CR cells present at birth die before the second postnatal week in mice (Del Rio et al., 1995; Soda et al., 2003), some CR cells survive to adulthood (Chowdhury et al., 2010). CR cells extend long horizontal axons and form synaptic contacts

with dendrites of pyramidal neurons (Marin-Padilla, 1998; Meyer et al., 1999; Soriano and Del Rio, 2005; Villar-Cervino and Marin, 2012) and express Reelin, p73 (Trp73) and/or calretinin, and CXCR4, depending on their subtype of origin (De Bergeyck et al., 1998; Del Rio et al., 1995; Ogawa et al., 1995; Stumm et al., 2003). CR neurons were originally identified by their unique morphology and distribution within the marginal zone of developing human neocortex (reviewed by Meyer et al., 1999). These neurons control the radial migration of projection neurons through their secretion of protein Reelin. However, recent reports also indicate their roles in proliferation and areal patterning of later-born projection neurons (Griveau 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) projection neurons. Layers II/III pyramidal neurons establish interhemispheric synaptic connections and mediate higher order information processing through the integration of bilateral cortical information. These neurons send axons to distant ipsilateral and contralateral neocortical areas: the latter of which are called callosal projection neurons (CPN) and connect the two cerebral hemispheres by extending axons through the corpus callosum (Fame et al., 2011). These neurons have relatively small, pyramidalshaped somata and confined dendritic trees, and they form axonal collaterals with neighboring cortical regions (Gilbert and Wiesel, 1979; Lund et al., 1979). During the early postnatal period, most layers II/III projection neurons express the transcription factors Cux1/2, Brn1/2, Satb2 and the non-transcription factors Inhba and Limch1 (Britanova et al., 2008; Franco et al., 2012; McEvilly et al., 2002; Molyneaux et al., 2009; Nieto et al., 2004). In rodents, the distinction between layers II and III is not as clear as in primates. However, a few genes, including Frmd4b, Nnmt, Chn2 and Lpl, are expressed in a restricted subset of layers II/III neurons during mouse development (Molyneaux et al., 2009). Importantly, lineage analysis using Cre recombinase expressed from the Cux2 gene locus (Cux2Cre/+ mice) has shown that Cux2-expressing cells predominantly contribute to layers II–IV neurons, which defines Cux2 as an UL neuron lineage marker (Franco et al., 2012). Neurons of layer IV, in turn, convey sensory information into the neocortex by receiving input from peripheral organs. These neurons function as high-fidelity gateway for sensory inputs, maintaining strict topographic organization and information transfer to a given neocortical area. The glutamatergic neurons of layer IV exhibit a variable dendritic pattern compared to other layers (Staiger et al., 2004). For example, in the somatosensory cortex, spiny stellate cells represent a distinctive class of glutamatergic neurons. These neurons differ in their morphology from the more abundant pyramidal neurons by the lack of a polarized apical dendrite and confine their dendritic arbor in the same layer, while typically projecting axons to layers II/III within the column (Anderson et al., 1994; Martin and Whitteridge, 1984; Yoshimura et al., 2005). In contrast to other layer neurons, the number of layer IV neuron specific markers is limited of which Rorb, Unc5d and Kcnh5 (or Eag2) have been identified so far (Ludwig et al., 2000; Saganich et al., 1999; Schaeren-Wiemers et al., 1997; Zhong et al., 2004). Neurons of layer V, together with layer VI neurons, are grouped as deep-layer (DL) neurons and consist mainly of corticofugal projection neurons. Layer V neurons project to the brainstem and spinal cord, and express Fezf2 and Ctip2, and a subset of these express ER81 (Chen et al., 2005a,b; Inoue et al., 2004; Molnar and Cheung, 2006; Molyneaux et al., 2005; Yoneshima et al., 2006). Although layer V neurons are mostly subcerebral projection neurons (SCPNs), it is notable that approximately 20% of neocortical CPNs localize in layer V, and these neurons are similar to layers II/III CPNs in their molecular expression and connectivity (Molyneaux et al., 2009). Notably, layer V contains large pyramidal neurons that are disposed


in radial clusters; these neurons express specific subsets of genes such as Ctip2 and Id2, and are segregated from CPNs that occupy the same layer (Kwan et al., 2012; Maruoka et al., 2011). These observations imply that projection neurons of common molecular profiles are further organized into microdomains within the same layer. In turn, layer VI neurons establish corticothalamic projection neurons (CThPNs) and express Tbr1, Zfpm2, and Sox5 (Hevner et al., 2001; Kwan et al., 2008). Layer VI neurons exhibit greater variability in their dendritic patterns; however, the correspondence of their morphology and gene expression is less defined compared to other layers. Subplate neurons (alternatively called layer VIb or layer VII neurons), are also early-generated neurons in the neocortex that have undergone expansion during mammalian evolution (Montiel et al., 2011; Smart et al., 2002). Subplate cells are identified by their deepest position in the cortical plate and expression of CTGF, Cplx3, and Lpar1 during the perinatal periods (Hoerder-Suabedissen and Molnar, 2013); however, earlier, they share several molecular features with layer VI neurons (Hevner et al., 2001; Kwan et al., 2008; Lai et al., 2008). Subplate neurons serve as initial scaffolds for thalamic afferents into the neocortex and provide the earliest excitatory inputs into the neocortex (Ghosh et al., 1990; Kanold et al., 2003). While subplate neurons are also considered to be largely transient cells in mice (Price et al., 1997), a proportion of these cells remain in postnatal primate cortices (Judaˇs et al., 2010; Kostovic and Rakic, 1980). Thus, subplate cells may also function beyond early circuit formation.

3. Spatial origins of neocortical glutamatergic neurons The intricate cytoarchitecture of the neocortex has long attracted neuroscientists to investigate how the diversity of neurons are created and how their precise integration is coordinated during development. For this, it is worthwhile to consider the mechanisms by which neocortical subtypes are generated along both the spatial and temporal axis. Despite its complexity, the neocortex starts as a simple sheet of neuroepithelium at the anterior end of the neural plate of which the dorsal sector of the telencephalon becomes the pallium. The pallium is divided into four proliferative zones according to molecularly definable boundaries: medial, dorsal, lateral and ventral pallium (Fig. 1A). Here, we focus exclusively on the establishment of these subdivisions in threedimensions to address the neocortical subtypes that arise from each sector. Extensive studies in mice have shown that early forebrain patterning is established between 3 and 6 somite stages (∼embryonic day (E)8.0) through the reciprocal action of transcription factors and morphogens. The anterior neuraxis is instructed through the head organizer activity of the anterior visceral endoderm. Subsequently, Otx2 (induced by the anterior neuroectoderm enhancer, Fig. 1A and B) establishes the forebrain and midbrain territories through an antagonistic effect on Gbx2 (∼6-somite stage) (Inoue et al., 2012; Kurokawa et al., 2004, 2014; Millet et al., 1999). Within the forebrain, the expression of Emx2 (3-somites∼) (Simeone et al., 1992; Suda et al., 2001) and Pax6 (late 4-somites∼) (Inoue et al., 2000) functions redundantly to establish the caudal forebrain, which contributes to the medial and ventral pallium (shown in green and light blue in Fig. 1A and B) and diencephalon (Kimura et al., 2005). In parallel, rostrally, Six3 is expressed at the anterior neural plate after E8.2 (Oliver et al., 1995) (Fig. 1B) and represses Wnt1 to establish the rostral forebrain domain (Lagutin et al., 2003). The expression of Fgf8 in the anterior neural ridge (ANR) commences at approximately 4-somites (Suda et al., 1997), which induces Foxg1 in the Six3-expressing domain and establishes the dorsal pallium and subpallium (Kobayashi et al., 2002; Lagutin

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et al., 2003) (Fig. 1B). The boundary between the pallium and subpallium (pallial–subpallial boundary; PSB) is established through cross-repression between Gli3 and Shh, and Fgf8 expression (Gutin et al., 2006; Rallu et al., 2002). Through these interactions, the border between the Pax6+ pallium and the Nkx2.1+ subpallium is first established around E9.5 (Shimamura et al., 1995) (Fig. 1B), which is subsequently replaced by a Pax6/Gsx2 boundary by E12.5 (Yun et al., 2001). After this, the entire pallium is defined by Pax6 expression in the progenitors and Tbr1 expression in the postmitotic neurons (Puelles et al., 2000), although Tbr1 is downregulated in many of the layers II–V neurons (Han et al., 2011). Notably, although the expression of Emx2 and Pax6 extends into the dorsal pallial territory, the enhancer that drives expression in the caudal forebrain and dorsal pallium appears to be different (Kammandel et al., 1999; Kleinjan et al., 2004; Theil et al., 2002). Emx1 is further restricted in its lateral extent (Fernandez et al., 1998), where it delineates an expression boundary between the lateral and ventral pallium (Puelles et al., 2000) (Fig. 3C, left panel). The medial pallium, in turn, is defined by the expression of multiple Wnts (Wnt3a, Wnt5a and Wnt2b) by E9.5 (Parr et al., 1993) (Fig. 1A and B). Currently, the molecular boundary that delineates the lateral and dorsal pallium progenitors is not clear; it is suggested that Cadherin 8 is expressed higher in the lateral pallium than that of the dorsal pallium derivatives (Medina et al., 2004). Based on gene expression and genetic fate-mapping studies, it is clear that most neocortical glutamatergic neurons arise from progenitor cells of the Emx1-positive Wnt3a-negative dorsal pallial sector (Gorski et al., 2002; Louvi et al., 2007) (Fig. 3C, left). The medial and lateral/ventral pallium, in turn, gives rise mainly to hippocampus and olfactory cortex/amygdala neurons (Medina et al., 2004). There are two exceptions, however, where these sectors contribute to neurons of the neocortex: these are the early-generated neurons, CR cells and Dbx1-expressing transient glutamatergic neurons (Garcia-Moreno et al., 2007; Teissier et al., 2010, 2012). After a long assumption that CR cells are generated from the dorsal pallium, Meyer was the earliest to suggest that Reelin-expressing CR cells arise from a discrete pallial sector in the neuroepithelium and enter the neocortex by tangential migration (Meyer et al., 1999). Later, p73 was identified as an alternative CR cell marker and demonstrated a similar tangential spread from the medial and ventral pallium to the dorsal pallium (Meyer et al., 2002). The experimental evidence for non-dorsal pallium-derived CR cells first came from exo utero electroporation of LacZexpressing plasmids, where cells labeled in the medial pallium with LacZ spread tangentially into the surface of the dorsal pallium (Takiguchi-Hayashi et al., 2004). Later, genetic fate-mapping using Wnt3aCre/+ mice (Yoshida et al., 2006) and Dbx1Cre/+ mice (Bielle et al., 2005) revealed the medial and ventral pallium as source of CR cells. It is important to clarify here that (1) the medial pallium contains the region of cortical hem and choroid plexus and (2) the ventral pallium connects caudally to the thalamic eminence and rostrally to the septum (Kimura et al., 2005; Puelles, 2011; Roy et al., 2013). Although these regions (cortical hem, choroid plexus, thalamic eminence) have been considered as independent sources of CR cells (Imayoshi et al., 2008; Tissir et al., 2009; Yoshida et al., 2006), they correspond to the derivatives of the caudal forebrain, which are initially established by Emx2 and Pax6 (Kimura et al., 2005) (Fig. 1B). Two transcription factors, Foxg1 and Lhx2, in turn, establish the dorsal pallium progenitors. Foxg1, a forkhead-box family protein, marks the anterior forebrain from early vertebrates (Bardet et al., 2010; Toresson et al., 1998). Consistent with its expression, Foxg1 has an evolutionary conserved role in vertebrate telencephalic development; in Xenopus, zebrafish, chickens and mice, Foxg1 regulates telencephalic growth (Ahlgren et al., 2003; Hanashima et al.,

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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.


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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.

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2002; Regad et al., 2007) and patterning (Manuel et al., 2010; Roth et al., 2010) through antagonizing TGF-b/Smad pathways (Seoane et al., 2004) and repressing p27Kip1 expression (Hardcastle and Papalopulu, 2000). Studies in mice and chickens show that Foxg1 is induced by Fgf8 within the Six3-expressing domain (Kobayashi et al., 2002; Shimamura et al., 1995); however, an interesting regulatory conservation is reported in hemichordates (Pani et al., 2012). Studies in zebrafish reveal that Foxg1 establishes the dorsal pallium and subpallium by repression of the Wnt8b promoter through its binding to a vertebrate-conserved sequence (Danesin et al., 2009). Notably, studies using conditional mutant mice identified multiple Foxg1-repressed target genes expressed in both the medial and ventral pallium (Eya2, Dmrt3, Zic3, Ebfs), and some of these binding sites were specific to mammals (Kumamoto et al., 2013). Consequently, in the absence of Foxg1, the medial and ventral pallium expands at the expense of the dorsal pallium (Danesin et al., 2009; Kumamoto et al., 2013) (Fig. 2C). Lhx2 is a LIM-homeodomain transcriptional factor, which is expressed in a medial-high to lateral-low graded pattern across the dorsal pallium, and it delineates the boundary with the medial pallium (Monuki et al., 2001) (Fig. 3C). Both Lhx2 constitutive knockout mice and chimera studies using Lhx2−/− wildtype cells indicate that Lhx2 is required for dorsal pallium specification, and its absence results in the expansion of both the medial and ventral pallium at the expense of the dorsal pallium (Bulchand et al., 2001; Mangale et al., 2008). Notably, the requirement for Lhx2 in the dorsal pallium has a restricted temporal window; whereas removal of Lhx2 before E10.5 converts it to both a medial and lateral pallium fate, conditional knockout between E10.5 and E11.5 results in expansion of the lateral and ventral pallium but not the medial pallium, and after E11.5, Lhx2 is no longer required to maintain the dorsal pallium identity (Chou et al., 2009; Mangale et al., 2008). Within the forebrain, the expression of Emx2 (3-somites∼) and Pax6 (4-somites∼) precedes that of Foxg1 and Lhx2, which commences around 5-somites (E8.0) and E8.5, respectively (Mangale et al., 2008; Tao and Lai, 1992) (Fig. 1B). This implies that Foxg1 and Lhx2 specify the dorsal pallium after the medial and ventral pallium is established (Fig. 1B). Genetic fate-mapping and loss-of-function analysis further imply that these two (rostral and caudal) forebrain territories are derived from a distinct lineage; the compound loss of Emx2 and Pax6 results in the loss of the medial and ventral pallium but not the dorsal pallium or subpallium (Kimura et al., 2005). Notably, while Foxg1 and Lhx2 are both required to establish the dorsal pallium, at caudal levels, Foxg1 delineates a sharp border at the ventral pallium and exhibits a gradient at the medial pallium; Lhx2 shows the opposite trend with a sharp boundary at the medial pallium and a graded expression at the lateral/ventral pallium (Kumamoto et al., 2013; Monuki et al., 2001; Allen Brain Atlas, http://www.brain-map.org). Currently, evidence for genetic interactions between Lhx2 and Foxg1 is lacking: knockout and chimera studies have shown that within the cortex Foxg1−/− cells express Lhx2 caudally, whereas Lhx2−/− progenitors retain Foxg1 expression laterally (Mangale et al., 2008; Muzio and Mallamaci, 2005). This implies that Foxg1 and Lhx2 function cooperatively but independently to establish the dorsal pallium identity. This is consistent with their distinct temporal requirements for cortical specification. The removal of Foxg1 at E13 is sufficient to convert the dorsal pallium to a medial and ventral pallium identity (Hanashima et al., 2007; Kumamoto et al., 2013), but the conditional removal of Lhx2 exhibits an early (approximately E11.5) competence window for a dorsal to lateral/ventral pallium conversion (Chou et al., 2009). Another difference between Foxg1 and Lhx2 is that while Lhx2 is dispensable for subpallium development (Bulchand et al., 2001), Foxg1 is essential for ventral telencephalic identity (Martynoga et al., 2005). Thus, the absence of obvious ventral pallium expansion in Foxg1−/− cells

appears to be secondary to the loss of ventral gene expression (Fig. 1A and B). These observations are consistent with the primary targets of Foxg1 and Lhx2 being largely non-redundant (Hou et al., 2013; Kumamoto et al., 2013; Tao and Lai, 1992). 4. Temporal specification of neocortical glutamatergic subtypes 4.1. Cell competence and lineage of neocortical subtypes – a question revisited At the time each pallium domain is established, the neuroepithelial cells of the dorsal pallium give rise to radial glial cells (RGCs), which are more fate-restricted progenitors. The successive replacement of neuroepithelial cells to RGCs may be instructed by several molecules (Kang et al., 2009; Sahara and O’Leary, 2009) and terminates the competence of dorsal pallium progenitors to respond to the loss of Lhx2 (Chou et al., 2009) but still requires Foxg1 (Hanashima et al., 2004). The earliest neurons in the neocortex appear at the surface of the dorsal pallium around E10–E11 and are tangentially migrating CR cells generated from the medial and ventral pallium, which form the preplate. After CR cell production, most neocortical glutamatergic neurons arise from the RGCs of the dorsal pallium, which migrate radially toward the pia and position themselves beneath the CR cells. Neurons are generated successively and migrate past the pre-existing, early-born neurons and allocate to the more superficial layers in an “inside-out” distribution, a unique pattern observed in the mammalian neocortex (Cooper, 2008; Hevner et al., 2003). Based on both in vitro and in vivo analysis, it has been suggested that the sequential generation of layer subtypes is regulated by an intrinsic program that switches progenitor cell competence over time. In vivo clonal analysis demonstrated that a common progenitor could contribute to neurons that encompass both deep and upper cortical layers (Luskin et al., 1988; Price and Thurlow, 1988; Reid et al., 1995; Walsh and Cepko, 1988, 1992). In vitro, DL neurons were commonly generated after fewer cell divisions than UL neurons, and progenitors from later-stage embryos were more restricted in their ability to generate earlier-born neuronal subtypes in vitro (Shen et al., 2006) and in vivo (Frantz and McConnell, 1996; McConnell, 1988; McConnell and Kaznowski, 1991). Cortical cells derived from mouse embryonic stem cells demonstrated that the temporal order by which stem cells generate neocortical glutamatergic subtypes could be replicated in vitro (Eiraku et al., 2008; Gaspard et al., 2008). These studies implied that the defined temporal order of projection neuron subtypes in the neocortex is controlled by intrinsic changes in progenitor cell competence over time. In this regard, recently, two alternative perspectives concerning the lineage of neocortical neurons have been proposed. Cux2, which is expressed in layers II–IV neurons in the mature neocortex, is expressed at a low level in RGCs at early embryonic stages. Using an inducible Cre recombinase knocked into Cux2 locus (Cux2CreER/+ ), a subset of RGCs was labeled by the recombination of a reporter with tamoxifen administration at E10.5; however, these progenitors mainly contributed to UL neurons (Franco et al., 2012). These results implied that a subpopulation of early cortical progenitors are dedicated to produce UL neurons but are restricted in their differentiation until the appropriate timing at a later corticogenesis period. This view is somewhat different from a lineage study using a Fezf2 BAC-transgenic Cre mouse line, which revealed that Fezf2-expressing progenitors can mark DL–UL-glia clones during the early corticogenesis phase and UL-glia clones at late corticogenesis phase (Guo et al., 2013). Although a simplistic interpretation of these results is that neocortical progenitors comprise both lineagerestricted and progressively restricted clones, the entire picture


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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 requires an unbiased and comprehensive clonal analysis to assess the relative contribution of each lineage in the mature neocortex. Such experiments will also provide insights into the mechanisms that underlie the precise connectivity between clonally related sister DL and UL projection neurons (Yu et al., 2009, 2012). 4.2. Genetic network underlying neocortical subtype segregation Despite the ambiguity of their lineage relationships, molecular mechanisms that segregate layer neuron subtype identities have been made clearer. Genetic studies have shown that the principal

layer subtypes of the cerebral cortex are established with a closed transcriptional network (Alcamo et al., 2008; Bedogni et al., 2010; Britanova et al., 2008; Chen et al., 2008; Han et al., 2011; McKenna et al., 2011; Srinivasan et al., 2012). Within these, repressor networks are the major regulatory cascades responsible for segregating 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 (Alcamo et al., 2008; Chen et al., 2008; Han et al., 2011; McKenna et al., 2011). For example, in Fezf2−/− knockout mice, Satb2+ CPNs and Tbr1+ CThPNs appear at the expense of SCPNs (Bedogni et al., 2010; Chen et al., 2005a; McKenna et al., 2011; Molyneaux et al.,

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2005), while forced expression of Fezf2 is sufficient to reprogram layers II/III CPNs and layer IV neurons to layer V/VI corticofugal neuron identity (Chen et al., 2005b; De la Rossa et al., 2013; Rouaux and Arlotta, 2013). In Tbr1−/− mice, DL neurons upregulate Fezf2 expression and project inappropriately to the pons (Han et al., 2011; McKenna et al., 2011). In Satb2−/− mice, Ctip2+ SCPNs increase (Britanova et al., 2008). Of these transcription factors, only Fezf2 is expressed in both progenitors and post-mitotic neurons (Hirata et al., 2004), whereas others are only detectable in post-mitotic cells (Alcamo et al., 2008; Arlotta et al., 2005; Britanova et al., 2008; Hevner et al., 2001). Furthermore, the segregation of these markers is only evident in postmitotic neurons: E13.5-born DL neurons initially co-express Satb2 and Ctip2, but later they are segregated into CPN and SCPN subtypes (Alcamo et al., 2008; Srinivasan et al., 2012). Sox5, Fezf2 and Ctip2 are also coexpressed in many young corticofugal neurons of layers V/VI and SP. However, as corticogenesis proceeds, Sox5 expression in post-mitotic cells represses Fezf2 expression in layer VI neurons (Kwan et al., 2008; Lai et al., 2008; Srinivasan et al., 2012). Therefore, it appears that some of these commitments take place at postmitotic levels. However, since the expression of many transcription factors is downregulated during migration, the extent of cell fate decisions controlled at progenitor levels is not clear. In this regard, Foxg1 plays a key role in early fate transition within progenitors. Conditional removal of Foxg1 in DL progenitors switches these progenitors to adopt a CR cell fate; however, its removal in postmitotic neurons does not revert DL neurons into CR cells (Kumamoto et al., 2013). In turn, delayed induction of Foxg1 at E14.5 in vivo reveals that CR progenitor cells can generate Ctip2+ /Fezf2+ DL neurons at a progressively later stage of neocorticogenesis (Kumamoto et al., 2013) (Fig. 2A and B). Genome-wide analysis reveals that the onset of Foxg1 expression represses multiple transcriptional factors (Dmrt3, Eya2, Ebf2/3, and Zic3) that are expressed in the progenitors of CR cells (Fig. 2C). These results indicate that although the initial medial/ventral and dorsal pallium territories are established independently, the progenitor cells that generate CR neurons and DL neurons are interconvertible; their competence switch is strictly regulated by a single transcription factor, Foxg1 (Fig. 2A and B). Taken together, the specification of neocortical layer neurons involves the following two steps: (1) the suppression of a default CR cell identity and commitment to projection neuron fate through Foxg1-mediated gene cascade and (2) cross-regulatory determination of layer subtypes through subtypespecific transcription factors (Fig. 2C).

5. The mammalian-specific regulation of neocortical subtype specification To what extent is the developmental program that directs patterns of neurogenesis and their assembly ‘neocortex’ specific? To discuss this, it is necessary to define the homologous subtypes of neocortical neurons and their progenitors across amniotes. Because of the nature of evolution, such identification must rely on multiple criteria. Indeed, there is still a debate concerning the cross-species homology between the pallial neuron subtypes. This is because, at a glance, the cytoarchitecture of the cerebrum is highly variable between amniotes; reptiles use a mono-layered cortex for their information processing (Cheung et al., 2007; Nomura et al., 2013), whereas birds undergo nucleotypic organization to form mature cerebral circuits (Jarvis et al., 2013; Montiel and Molnar, 2013; Nomura et al., 2008). Dugas-Ford et al. (2012) took particular interest in the gene expression and connectivity between neurons of the neocortex and sauropsid pallium. In particular, they focused on thalamorecipient neurons and SCPNs; the former corresponds to layer IV and

the latter to layer V projection neurons in mammals. In avians, visual information from the optic tectum is relayed by the nucleus rotundus of the thalamus and enters the entopallium, and auditory information is relayed through the thalamic auditory nucleus to neurons in Field L (Fig. 3B). These thalamorecipient neurons express Rorb, a representative marker for neocortical layer IV neurons. In turn, at least three of the neocortical layer V markers, Er81, Fezf2 and Pcp4, are expressed in the chicken arcopallium in the avian dorsal ventricular ridge (DVR; a characteristic protrusion into the lateral ventricle in sauropsids) and hyperpallium (Fig. 3B). In the turtle, the rostral area D2 corresponds to input sensory zones of the anterior DVR and expresses Rorb and Eag2 (Dugas-Ford et al., 2012; Ulinski, 1986) (Fig. 3B). By contrast, the layer V marker ER81 labels the intermediate and posterior fields of area D2, which are expressed complementary with Rorb at a single cell resolution (Dugas-Ford et al., 2012) (Fig. 3B). Satb2- and Ctip2-expressing neurons also comprise largely complementary populations in the gecko pallium (Nomura et al., 2013), although the projection targets of these neurons are still unclear. These observations imply that in sauropsids, the homologous subtypes may allocate across multiple pallial sectors and are not solely dorsal pallium derivatives. The correspondence of a few genes may be insufficient to claim homology between mammals and sauropsid pallial neuron subtypes. In this regard, recently, a comprehensive transcriptome analysis has been performed by two groups (Belgard et al., 2013; Chen et al., 2013; Jarvis et al., 2013). Based on the expression analyses of 52 genes in the zebra finch, (Jarvis et al., 2013) proposed a new compartment model in avians based on gene expression similarities between subdomains of the bird pallium and mammalian neocortex. Comparative transcriptomics of over 5000 genes in the adult chick and mouse cerebrum also revealed some convergence between the different sectors of these species, but also highlighted divergent molecular characters (Belgard et al., 2013; Montiel and Molnar, 2013). Interestingly, in vitro clonal analysis in the chick implies conservation between the temporal neurogenesis programs of mice and chicks (Suzuki et al., 2012). In these experiments, chick pallial progenitors produce layer specific subtypes in a similar chronological sequence in vitro as those observed in mammals (Suzuki et al., 2012). Furthermore, recent birthdating studies in the gecko showed that the Satb2- and Ctip2-expressing cells in the dorsal pallium also exhibited a similar trend in their temporal production, where many Ctip2+ cells are generated earlier than Satb2+ cells (Nomura et al., 2013). These results raise an intriguing 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 the temporal programs of neuronal subtypes are conserved, the mechanisms that underlie the changes in the final configuration of neuronal subtype allocation within each vertebrate class appear to rely on other elements. For this, at least two changes between mammals and sauropsids can be argued. One possibility is that each pallial sector may undergo disproportional expansion in sauropsids, thereby spatially modifying their neurogenesis program. It is important to note that in general, the rostrocaudal and dorsoventral patterning of the telencephalon is conserved across amniotes, and the expression of Pax6, Tbr1, and Emx1 and the emergence of the four pallial sectors are similar in both birds and reptilians (Puelles et al., 2000) (Fig. 3C). An exception is that the chick ventral pallium does not express Dbx1 as found in the mouse (Bielle et al., 2005) (Fig. 3C). Instead, the Pax6+ domain contacting the subpallium expresses Sfrp1 (von Frowein et al., 2002), a homologue of Sfrp2, which is expressed in the mouse ventral pallium (Assimacopoulos et al., 2003) (Fig. 3C). However, the subsequent transformation of each pallial sector to mature cerebral structures is quite distinct between mammals and sauropsids. While the contribution of the medial pallium to the hippocampus and


parahippocampal area, the lateral pallium to the olfactory cortex, and the ventral pallium to the pallial amygdalar nuclei is similar (Abellan and Medina, 2009), the avian dorsal pallium consists of the hyperpallium (also called the Wulst) and the ventral pallium largely contributes to the DVR (Bell et al., 2001; Striedter et al., 1998). The anterior DVR contains auditory, visual, and somatosensory recipient regions and the neurons of the posterior DVR projects to the ventromedial and lateral hypothalamus (Bruce and Neary, 1995a,b). Thus, neuronal components of similar properties with respect to their input/output connections have undergone distinctive spatial arrangements between amniotes, which may involve the modification of the production and migration program of neuronal subtypes resulting in the expansion of neurons along radial dimensions in mammals. A second possibility is that mammalian-specific neuronal components may impact the ultimate laminar and areal organization that characterizes the neocortex. A century after the original description by (Retzius, 1893) and (Cajal, 1899), CR cells were brought to attention by their critical roles in instructing radial neuron migration and ‘inside-out’ six-layer neocortex formation (Rice and Curran, 2001; Tissir and Goffinet, 2003). Although the original phenotype of the spontaneous mutant mice for Reelin was reported earlier (D’Arcangelo et al., 1995; Ogawa et al., 1995), the precise mechanisms of Reelin action in neuronal migration have been unraveled only recently (Franco et al., 2011; Gil-Sanz et al., 2013; Sekine et al., 2012, 2014). Indeed, expression studies in chick, turtle, crocodile and lizard shows that Reelin-positive, CR-like neurons are underrepresented in the sauropsid pallium, whereas the number is increased in humans (Bernier et al., 1999, 2000; CabreraSocorro et al., 2007; Goffinet et al., 1999; Meyer, 2010; Tissir et al., 2003). The correlation between an increase in the medial pallium during evolution also suggests a concerted role in the evolutionary increase of CR cells (Meyer, 2010). In lizards, the cells expressing p73 in the dorsal pallium appears much fewer than that of Reelin-positive cells (Cabrera-Socorro et al., 2007), implying that the regulation of these two genes in CR cells may be different in reptiles. The functional significance of CR cells is supported by an experimental evidence in which Reelin-introduced COS7 cell were transplanted into quail cortical slices, which prompted radial fibers to extend long processes toward the pial surface, a character for mammalian neocortical progenitors (Nomura et al., 2008). While these studies are indicative that the acquisition of CR cells was a critical event in establishing a laminated neocortex system, it is also noteworthy that reducing the number of CR cells in mice by genetic ablation (35% reduction in Wnt3aCre/+ ; Rosa26loxp-stop-loxp-dta double heterozygous mice and 84% reduction in Wnt3aCre/+ ; DeltaNp73Cre/+ ; Rosa26loxp-stop-loxp-dta triple heterozygous mice) results in an overall normal laminar organization at birth (Tissir et al., 2009; Yoshida et al., 2006). These results imply that the significant increase in CR cell number and diversity during evolution may serve roles beyond lamination to instruct the neocortical cytoarchitecture. Interestingly, the binding sequences of Foxg1 to its target CR cell genes are only conserved in mammals (Kumamoto et al., 2013). Therefore, the regulation of CR cells by Foxg1 in itself may have been a novel acquisition of the mammalian species. Notably, the expression of Foxg1 appears with a shorter delay to that of Emx2 in chick than in mice; Foxg1 is detectable as early as Hamburger–Hamilton stage (HH) 6 in the chick anterior neural plate and is highly expressed at HH8, whereas Emx2 expression is low at HH8 and increases after HH12 (Bell et al., 2001). In mouse, the onset of Foxg1 expression (5-somite stage) (Kobayashi et al., 2002; Lagutin et al., 2003) follows that of Emx2 (3-somites) (Simeone et al., 1992; Suda et al., 2001) expression. The differences in their expression timing may thus influence the early patterning of respective dorsal and medial pallial territories (Fig. 1B), thereby contributing

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to the size expansion of the cortical hem and CR cell number in mammals. 6. The evolvability of the neocortex – future perspectives As mentioned, CR cells may be one feature that characterizes the mammalian neocortex within the amniote brains. Until recently, the identification of CR cells has relied on the expression of Reelin, which is the only marker identified to be expressed in all CR cell subtypes in mammals (even though Reelin is expressed in non-CR cells, including interneurons) (Soriano and Del Rio, 2005; Villar-Cervino and Marin, 2012). However, the identification of multiple subtypes of CR cells with distinct molecular features naturally underscored the complexity of CR cells and raised a question of how and why such diversity of CR cells has been created. Regarding this, two nonexclusive mechanisms can explain their diversity. One is that the presence of specific morphogens in each pallial sector may introduce a regional character to the CR cell subtypes. For example, the medial pallium is the source of Wnts and Bmps, and the ventral pallium expresses Sfrp2 caudally and Fgf8, 17, and 18 rostrally. These may induce differential gene expressions in regional CR cells. The second explanation is that CR cells may represent a default state of cortical progenitors; therefore, these neurons retain a wider molecular repertoire due to the higher number of accessible chromatin at the earliest competent state. Progression of the corticogenesis program may restrict the configuration of the chromatin and limit the number of genes expressed in subsequent-born projection neurons. Are multiple origins and subtypes of CR cells a consequence or a cause of sauropsid-to-mammalian brain conversion? It is possible, that the neocortical evolution may itself require the increase in both the number of CR cells and their molecular diversity. Pollard et al. (2006) scanned ancestrally conserved genomic regions to search for regions that showed significant acceleration of substitutions in the human lineage, and found that many of these human accelerated regions (HARs) are associated with genes involved in transcriptional regulation and neural development. In particular, a 118 bp HAR1 region showed the most accelerated change and is expressed specifically in CR cells in human embryonic neocortex (Pollard et al., 2006). This suggests that molecular heterogeneity of CR cells may be associated with new functions during neocortical evolution. Consistent with this view, the manipulation in the number and distribution of CR cells can modify progenitor properties in a region-specific manner, implying that CR cell subtypes may serve as mediators of early neocortical patterning (Griveau et al., 2010). As opposed to the projection neurons that have discerned functions in the neocortical circuit formation, the extent of heterogeneity and functional repertoire of early-born neurons is still largely unknown, partly because the molecular diversity of these subtypes has only been appreciated recently (Griveau et al., 2010; Hoerder-Suabedissen and Molnar, 2013; Kumamoto et al., 2013). Further investigations into the molecular functions of CR cells will provide insights into the ontogeny and elaboration of a mammalian-specific neocortical circuit formation. Currently, the mechanisms of mammalian neocortical subtype specification stand on the premise that the molecules and their activity identified in mice are generally conserved among mammals. However, the size of the neocortex differs substantially in different species ranging from soricomorpha to cetaceans (Catania et al., 1999; Naumann et al., 2012). Taking this into consideration, the regulation of the production of neocortical subtypes requires a developmental process in the broader context of evolution that ultimately balances the numbers of functionally distinct neurons among different species. Hence, such mechanisms must utilize a system adaptable to changes in cortical size during mammalian evolution. For example, Foxg1 target transcription factors exhibit a caudal-to-rostral gradient expression within the pallium,

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implying that the onset of Foxg1 expression induced by anterior FGF8 (Shimamura and Rubenstein, 1997) might repress early cell competence in an opposed rostral-to-caudal gradient, resulting in a spatiotemporal switch from CR cell to DL neuron identity (Fig. 2C). Therefore, the expansion of mammalian cortical size during evolution may have incorporated efficient, compensatory mechanisms to generate sufficient numbers of CR cells prior to the onset of DL neurogenesis, which requires CR cells for their radial migration. How is the neuronal number of other layer subtypes controlled? Higher-order mammals, such as primates, have large gyrencephalic neocortex. Recent studies have shown that the disproportionate expansion of neocortical surface area and neuron number during evolution relies on the acquisition of novel progenitor types and additional germinal zones including outer RGCs and SVZ (Betizeau et al., 2013; Fietz et al., 2010; Geschwind and Rakic, 2013; Hansen et al., 2010; Lui et al., 2011; Shitamukai et al., 2011). Therefore, the regulation of a switch from DL to UL neurogenesis will also require a system that is adaptable to increases in cortical size, gestational period, cell cycle, and division modes during mammalian evolution (Fietz and Huttner, 2011; Lui et al., 2011). The mechanisms that balance the production of UL to DL neurogenesis await further investigation, including the segregation timing of their lineages (Franco et al., 2012; Guo et al., 2013). 7. Conclusions The neocortical structure is specialized for processing an extensive range of information and complex behaviors that are unique to mammalian vertebrates. At molecular levels, the mechanisms underlying the specification of neuronal subtypes have begun to unravel; however, that much remains to be explored about when and how these fate commitments takes place. Although this review highlights the significance of neocortical assembly in mammals, these insights also imply that neuronal specification and patterning may involve species-specific regulatory mechanisms in reptiles and birds. Of course, one cannot argue the presence of higher cognitive processing in birds and reptiles (Reiner and Northcutt, 2000) despite the lack of distinctive laminated cytoarchitecture. While an anatomically remote structure such as the DVR makes the direct comparison of neuronal subtypes between mammals and sauropsid brains devious, combinatorial approaches including molecular function and lineage analysis will eventually connect their ontogeny. Detailed understanding of the roles of mammalianspecific neuron population such as CR cells will likely provide new insights into neocortical development. Taking into account all these questions, future experiments addressing how the neocortex is established from an ancestral dorsal telencephalon will place the critical piece of the puzzle concerning the functional significance of the human neocortical circuit. Acknowledgements We thank T. Hirasawa and S. Kuratani (RIKEN CDB) for providing us with the neonate Chinese soft-shelled turtles (Pelodiscus sinensis). We thank all members of the Hanashima laboratory for insightful comments and discussions. This study was supported through a Grant-in-Aid for Scientific Research on Innovative Areas “Neural Diversity and Neocortical Organization” from the MEXT of Japan (25123725) to C.H. References Abellan, A., Medina, L., 2009. Subdivisions and derivatives of the chicken subpallium based on expression of LIM and other regulatory genes and markers of neuron subpopulations during development. J. Comp. Neurol. 515, 465–501. Ahlgren, S., Vogt, P., Bronner-Fraser, M., 2003. Excess FoxG1 causes overgrowth of the neural tube. J. Neurobiol. 57, 337–349.

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G9a influences neuronal subtype specification in striatum.

Fate and freedom in developing neocortical circuits.

Neuronal specification.

Tlx3 promotes glutamatergic neuronal subtype specification through direct interactions with the chromatin modifier CBP.

Microglia in neuronal circuits.

Corticothalamic Projection Neuron Development beyond Subtype Specification: Fog2 and Intersectional Controls Regulate Intraclass Neuronal Diversity.

Postmitotic control of sensory area specification during neocortical development.

WDFY3) is required for establishing neuronal connectivity in the mammalian brain.

Synthetic therapeutic gene circuits in mammalian cells.

Asynchronous Rate Chaos in Spiking Neuronal Circuits.

Imaging neuronal populations in behaving rodents: paradigms for studying neural circuits underlying behavior in the mammalian cortex.

Prefrontal neuronal circuits of contextual fear conditioning.

Timing control by redundant inhibitory neuronal circuits.

Metabolism: Altered neuronal circuits control metabolic fate.

A transcriptional hierarchy involved in mammalian cell-type specification.

Neuronal circuits: Connecting to innate knowledge.

Sculpting circuits: CRH interneurons modulate neuronal integration.

Specification of neuronal subtypes by different levels of Hunchback.

Developmental self-construction and -configuration of functional neocortical neuronal networks.

Circadian rhythms in neuronal activity propagate through output circuits.

Corrigendum: Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro.

Plasticity in the transcriptional and epigenetic circuits regulating dendritic cell lineage specification and function.

Systematic transfer of prokaryotic sensors and circuits to mammalian cells.

Organization and function of neuronal circuits controlling movement.