哺乳類大脳皮質の進化ー新たな研究戦略の展開 Evolution of the mammalian cerebral cortex -New research strategies
S1-4-1-1 祖先型脳からの哺乳類型大脳皮質の創出 Creation of the mammalian cerebral cortex from ancestor brains ○野村真1,2 ○Tadashi Nomura1,2 京都府立医科大学大学院医学研究科　神経発生生物学1, JST, さきがけ2 Dev Neurobiol, Grad Sch Med, Kyoto Pref Univ Med, Kyoto, Japan1, JST, PRESTO, Saitama, Japan2 The mammalian cerebral cortex has one of the most intricate architectures in the vertebrate central nervous system, which is characterized by a six-layered laminar structure and expanded surface areas. These anatomical hallmarks are constructed with large numbers of neurons of variety of subtypes, which are generated by the rapid expansion of neural stem/progenitor cells, and sequential production and migration of distinct neuronal subtypes during embryogenesis. However, evolutionary changes in developmental programs that created cortex-specific architectures are still unknown. In the last years, we have demonstrated that patterns of neuron subtype specification and amplitude of Reelin expression are critical to create a mammalian type cortical structure (Nomura et al. 2008; 2009). To further elucidate the evolutionary processes of the cerebral cortex, recently we analyzed cortical development of Madagascar ground gecko, a reptilian species that exhibits primitive cortical structures (Nomura et al. 2013, in press). Genetic manipulation of gecko corticogenesis unveiled unique characteristics of reptilian neural stem/progenitor cells and underlying molecular regulations. Base on these data, we discuss possible mechanisms created the mammalian cerebral cortex and homologous structures in other amniotes, and a new experimental strategy to understand the cortical evolution.	S1-4-1-2 脳の進化発生過程における動くシグナリングオーガナイジングセンターとしてのDbx1由来細胞の働き Functions of Dbx1-derived neurons as an ideal migrating signaling organizing center for brain evolution ○新井洋子1 ○Yoko Arai1, Alessandra Pierani1 IJM, CNRS, University Paris Dederot1 The cerebral cortex comprises several types of neural progenitors which generate neurons that migrate to form the cortical plate. In rodent, pioneering Cajal-retzius (CR) neurons migrate over long distances to cover the entire cortical surface. Molecularly distinct CR subtypes are generated from different signal organizing centers, (i) the pallial septum, (ii) the pallial-subpallial boundary (PSB) and (iii) the cortical hem from embryonic day 10 in mouse embryos. Dbx1, a transcription factor, is involved in the generation of septum and PSB-derived CR neurons and genetic ablation of Dbx1-expressing neural progenitors causes premature neurogenesis during development and arealization defects in the neonatal brain. To molecularly dissect this cell non-autonomous effect, a DNA microarray analysis was performed using isolated Dbx1-derived neurons. This showed that CR neurons express different morphogens that could affect neurogenesis. We thus hypothesize that Dbx1-derived CR neurons are ideal 'motile local signaling centers' which control neurogenesis. Growing evidences indicate that CR neurons have increased during brain evolution, however, little is known regarding which CR subtypes have increased and, further, how their contribution results in the formation of the species-specific brain. Our laboratory has shown that Dbx1 expression at the PSB was evolutionally acquired between chick and mouse, suggesting that modifications of the cis-element of the Dbx1 gene may have occurred during evolution, and could contribute to the increase in the number of Dbx1-derived CR neurons. To assess its potential importance during brain evolution, Dbx1 expression patterns in non-human primate, rhesus monkey and human were analyzed, together with gene manipulation by the over-expression of the primate-specific cis-element of the Dbx1 gene to generate transgenic embryos. This work hopes to understand how Dbx1 function has contributed to primate brain evolution.
S1-4-1-3 Area-specific coordinated changes in rates of proliferation and radial migration during development in the primate neocortex ○Colette Dehay1, Henry Kennedy1 Stem Cell and Brain Research Institute, Inserm U8461 The cytoarchitecture of the cerebral cortex is largely determined by variation of the number and density of neurons in individual layers. Cortical cytoarchitecture requires the fine spatiotemporal control of neuron production in the germinal zones and its coordination with radially directed migration. These two processes orchestrate the emergence of cortical layers and ultimately cortical circuitry. Our previous work has shown that adjacent areas showing different neuron number are generated by differences in the cell cycle parameters during corticogenesis .This area-specific modulation of rates of neuron production raises the question of whether rates of radial migration of postmitotic neurons are also area-specifically regulated, as suggested by previous static in vivo observations in the developing primate visual cortex.Using real time imaging on organotypic slices, we show that supragranular layer neurons exhibit area-specific radial migration kinetics linked to area-specific proliferation rates. These area-specific radial migration kinetics are stage-specific and are selectively observed in supragranular neurons, which are generated by OSVZ precursors during the second half of corticogenesis. Infragranular neurons, generated by VZ precursors, radially migrate with similar kinetics in both area 17 and area 18. Our result also show congruent variations in the expression level of cytoplasmic p27 and radial migration velocities.	S1-4-1-4 Mechanisms of specification of cortical neurons, from mouse to man ○Pierre Vanderhaeghen1 IRIBHM and Neuroscience Institute, Universite Libre de Bruxelles, Belgium1 The cerebral cortex consists of several hundreds of different types of neurons, organized into specific cortical layers and areas, that display specific profiles of gene expression, morphology, excitability and connectivity. The identification and characterization of factors capable of (re)specifying the identity of cortical neurons has important implications regarding our understanding of neurodevelopmental diseases and in the context of therapies for neurological disorders. Embryonic stem (ESC) and other pluripotent stem cells constitute a promising tool for the modelling and treatment of human neural diseases. We previously uncovered an intrinsic pathway by which pluripotent stem cells recapitulate in vitro the major milestones of cortical development, leading to the sequential generation of a diverse repertoire of neurons that display most salient features of genuine cortical neurons. Here we will describe how this reductionist system has allowed to dissect with great versatility the molecular and cellular mechanisms underlying cortical neurogenesis, through the identification of novel transcription factors involved in this process. Moreover, we will present novel data linking cortical development and evolution, as the mouse and human pathways of corticogenesis from pluripotent stem cells display many similarities but also striking differences related to species-specific developmental programmes.

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