大脳新皮質構築と回路形成機構―哺乳類特有の脳構造はどのように作られるのか？ Neocortical Development and Circuit Formation - How is the Mammalian-Specific Brain Structure Formed?
S2-4-1-1 Neural stem and progenitor cells and the development and evolution of the cerebral cortex ○Wieland Huttner1 Max Planck Institute of Molecular Cell Biology and Genetics1	S2-4-1-2 THE EARLIEST CORTICAL CIRCUITS ○Zoltan Molnar1 Department of Physiology, Anatomy and Genetics, University of Oxford1 The subplate zone is a highly dynamic transient sector of the developing cerebral cortex that contains some of the earliest generated neurons, and the first functional synapses of the cerebral cortex. Subplate cells have important functions in early establishment and maturation of thalamocortical connections, as well as in the development of inhibitory cortical circuits in sensory areas. So far no role has been identified for cells in the subplate in the mature brain and disease association of the subplate- specific genes has not been analyzed systematically. Here we present gene expression evidence for distinct roles of the subplate across development as well as novel molecular markers to extend the repertoire of subplate labels. Performing systematic comparisons between different ages (E15, E18, P8 and adult) we reveal the dynamic and constant features of the novel markers labeling subplate cells during embryonic and early postnatal development and in the adult. This can be visualized using the online database of subplate gene expression at https://molnar.dpag.ox.ac.uk/subplate/. We also identify embryonic similarities in gene expression between the ventricular zones, intermediate zone and subplate, and distinct postnatal similarities between subplate, layer 5 and layer 2/3. The genes expressed in a subplate- specific manner at some point during development show a statistically significant enrichment for association with autism spectrum disorders and schizophrenia. Our report emphasizes the importance of the study of transient features of the developing brain to better understand neurodevelopmental disorders.
S2-4-1-3 大脳新皮質構築を担う細胞分化決定機構 Neuronal specification in establishing mammalian neocortical circuits ○花嶋かりな1 ○Carina Hanashima1 理化学研究所発生・再生科学総合研究センター1 RIKEN CDB1 The functional integrity of mammalian brain systems depends on the precisely coordinated production of diverse neuron populations during development. Specifically in the neocortex, progenitors produce distinct subtypes in a stereotypical order to establish a characteristic six-layer structure. Although homologous domains exist in sauropsids, neither avian nor reptilian dorsal pallium exhibits identical laminar structure despite some of the common gene expressions. Therefore, an interesting question remains how the genetic program is uniquely orchestrated in mammals to regulate the number and subtypes of neurons to assemble an elaborate neocortical circuit. Although most cortical glutamatergic neurons arise from local progenitors that migrate radially and differentiate into projection neurons, some exceptions exist, in which early-born neurons originate within the surrounding pallial progenitors and invade the neocortex through a distinct migration mode. These cells have both mitogenic and patterning effects on later born projection neurons and are unique to mammalian vertebrates. In this regard, we recently demonstrated that Foxg1, a forkhead transcription factor expressed in the telencephalon, plays a key role in switching these glutamatergic subtypes. Here, using genome-wide transcriptome and ChIP assay, we show that Foxg1 binds to highly mammalian-conserved non-coding sequences to regulate early gene program in the mouse neocortex. Consistent with these data, comparative expression studies in chick and marmoset show that these genes are differentially regulated amongst the mammalian and non-mammalian vertebrates. These results indicate that the expansion of mammalian cortical size during evolution have co-opted efficient compensatory mechanisms to generate sufficient number and molecular diversity of early signaling cells prior to the onset of neocorticogenesis, which may be a critical step in directing a laminated neocortex from a common dorsal pallium.	S2-4-1-4 大脳皮質層構造の形成機構 Mechanisms of layer formation in the cerebral cortex ○仲嶋一範1 ○Kazunori Nakajima1 慶應義塾大学医学部1 Keio University School of Medicine1 Cortical neurons form the cortical plate (CP) in an inside-out manner; that is, earlier-born neurons form the deeper layers, whereas later-born neurons migrate past the existing layers and form the more superficial layers. Reelin, a glycoprotein secreted in the marginal zone (MZ), is crucial for this layering. To clarify the Reelin function in vivo, we expressed Reelin ectopically in the developing cortex, and found that Reelin caused the leading processes of migrating neurons to assemble in the Reelin-rich region, which in turn induced their cell bodies to form cellular aggregates around Reelin. The ectopic Reelin-rich region became cell-body-sparse and dendrite-rich, resembling the MZ, and the late-born neurons migrated past their predecessors toward the central Reelin-rich region within the aggregates, resulting in a birthdate-dependent inside-out alignment even ectopically. In the intermediate zone (IMZ) and CP, neurons migrate along the radial fibers (locomotion). On the other hand, when the leading process reaches the MZ, only the soma moves rapidly towards the top of the CP, while the tip of the process remains attached to the MZ (terminal translocation). We found that the outermost region of the CP is densely packed with immature neurons and possesses unique features distinct from the rest of the CP, and named this region the primitive cortical zone (PCZ). Dab1-knockdown (KD) neurons could not migrate past the immature predecessors within the PCZ, suggesting that Dab1 is essential for entry into the PCZ by terminal translocation. Sequential in utero electroporation experiments suggest that the PCZ is the pivotal region for the Dab1-dependent eventual inside-out lamination, and that switching of the migratory mode from locomotion to terminal translocation plays critical roles for the neuronal entry into this unique region. Molecular mechanisms that control this process will be discussed.
S2-4-1-5 Interkinetic nuclear migration through TAG-1-assisted progenitor elongation prevents neuroepithelial overcrowding and ensures neocortical histogenesis Interkinetic nuclear migration through TAG-1-assisted progenitor elongation prevents neuroepithelial overcrowding and ensures neocortical histogenesis ○宮田卓樹1 ○Takaki Miyata1 名古屋大学大学院医学系研究科1 Nagoya University Graduate School of Medicine1 Neural progenitors exhibit cell cycle-dependent interkinetic nuclear migration (INM) along the apicobasal axis. Despite recent advances in understanding its underlying molecular mechanisms, the processes to which INM contributes mechanically and the regulation of INM by the apicobasally elongated morphology of progenitors remain unclear. We found that knockdown of the cell-surface molecule TAG-1, which is enriched basally in early mouse cerebral walls, causes retraction of progenitors' basal processes. Basally disconnected stem-like progenitors failed to undergo basalward INM and overcrowded in the periventricular space. Surprisingly, the overcrowded progenitors left the apical surface and migrated into basal neuronal territories. These observations, together with in toto live imaging and physical tests, suggest that progenitors may sense and respond to excessive mechanical stress. Although the heterotopic progenitors unexpectedly remained stem-like, sequentially producing neurons until late embryonic period, histogenesis was severely disrupted. Thus, INM is essential to prevent nuclear/somal overcrowding, thereby ensuring normal brain histogenesis.

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