一般口演（Oral）

Oral Neurogenesis, Gliogenesis, Cellular Differentiation-3 一般口演神経発生・グリア発生・細胞分化-3

7月28日（日）11:50～12:05　第10会場（万代島ビル　6F　会議室） 4O-10a2-1 網膜ミュラーグリア細胞における転写因子Raxの機能解析 Akiko Ueno（上野明希子），Taro Chaya（茶屋太郎），Takahisa Furukawa（古川貴久）大阪大学蛋白質研究所 The paired-type homeobox transcription factor Rax (Retina and anterior neural fold homeobox) plays important roles in multiple processes of retinal development and photoreceptor maturation. Rax is well conserved among many species, from Drosophila melanogaster to humans. Mutations in the human RAX gene lead to microphthalmia and anophthalmia and Rax-deficient mouse embryos exhibit a complete loss of the optic vesicle and abnormal forebrain formation. We previously found that Rax is expressed in Muller glial cells in the adult mouse retina. Muller glia cells are retinal-specific glial cells and contribute to neurotransmission and the maintenance of the retinal structure. However, the functional roles of Rax in Muller glial cells are still unclear. To clarify the function of Rax in the developing and mature Muller glial cells, we generated inducible Rax conditional knockout (Rax iCKO) mice, in which Rax was inactivated specifically in Muller glial cells at the late developmental stage, postnatal day 4 (P4), or the mature stage, 1 month old (1M), by tamoxifen treatment. In this study, we report that gliosis of Muller cells increased in Rax iCKO mice when they were injected tamoxifen at P4. In contrast, no significant change was observed in Rax iCKO mice, treated with tamoxifen at 1M. These results suggest that the transcription factor Rax is dispensable for the maintenance and function of Muller glial cells after maturation, whereas Rax plays an important role in the maturation and function of Muller glia cells at the late stage of the developing retina. Our study sheds light on the functional roles of Rax in developing Muller glial cells.		7月28日（日）12:05～12:20　第10会場（万代島ビル　6F　会議室） 4O-10a2-2 ヒト固有遺伝子NOTCH2NLの神経幹細胞における分子機能 Ikuo K Suzuki（鈴木郁夫），Kazuo Emoto（榎本和生）東京大院理生物科学 Human had acquired a tremendously enlarged volume of the cerebral cortex during the recent evolution after the divergence from Chimpanzee. The molecular and developmental basis for this evolutionary innovation remain largely unclear. We found human-specific genes called NOTCH2NL, which had been originated by partial duplication of an phylogenetically conserved NOTCH2 gene in the common ancestor of modern and ancient human species and functionally expand cortical neurogenesis through the upregulation of Notch signaling in the cortical progenitor cells. NOTCH2NLB, demonstrating the highest level of expression during human fetal cortical neurogenesis among four NOTCH2NL paralogs, physically binds to and suppresses a Notch ligand DLL1 through its EGF repeats and consequently enhances Notch signaling activity in a cell autonomous manner. A remaining important question is how NOTCH2NLB regulates DLL1 function in the cortical progenitor cells. We found a clue that NOTCH2NLB inhibits the intracellular trafficking of DLL1 protein and affects both its trans and cis functions. These results indicate that NOTCH2NLB is functioning as a balancer of Notch ligands and receptors by masking ligand activity, because both Notch ligands and receptors are present and competing each other in each single progenitor. The evolutionary acquisition of NOTCH2NL expression in the fetal cortical progenitors may have upregulated the basal level of Notch receptor activity and thereby extend the period of neurogenesis.

7月28日（日）12:20～12:35　第10会場（万代島ビル　6F　会議室） 4O-10a2-3 細胞周期の抑制はNotchシグナルを活性化することで胎生期神経系前駆細胞の運命決定を制御する Yujin Harada（原田雄仁）¹，Mayumi Yamada（山田真弓）²，Itaru Imayoshi（今吉格）²，Daichi Kawaguchi（川口大地）¹，Yukiko Gotoh（後藤由季子）¹ ¹東京大院薬 ²京都大生命科学研究科 Adult neural stem cells (aNSCs) generate neurons that modify cognitive functions such as learning and memory. Our previous studies demonstrate that slowly-dividing neural progenitor cells (NPCs) exist in the embryonic ganglionic eminences and that a fraction of this population is destined to become aNSCs located in the subependymal zone (Furutachi et al., Nat. Neurosci. 2015). We found that these slowly-dividing cells highly express the CDK inhibitor p57 ^kip2 (p57) and that p57 is essential for quiescence of aNSC and these slowly-dividing embryonic NPCs. However, it remains unclear whether p57 influences the characteristics of aNSCs and these NPCs other than quiescence. In this study, we found that ectopic overexpression of p57 in the embryonic mouse neocortex led not only to cell cycle arrest but also to maintenance of the undifferentiated state of NPCs. This function of p57 appears to require the CDK domain. In addition, our results suggested that high level expression of p57 results in the activation of Notch signaling. Moreover, knockdown of Hey1 by RNA interference in part canceled the effect of p57 overexpression on the maintenance of the undifferentiated state. Our result suggests that high level expression of p57 activates Notch-Hey1 signaling and thus mediates the undifferentiated state of NPCs.		7月28日（日）12:35～12:50　第10会場（万代島ビル　6F　会議室） 4O-10a2-4 Hes1とAscl1が成体神経幹細胞の静止状態と活性化状態を制御する Risa Sueda（末田梨沙）¹，Itaru Imayoshi（今吉格）^1,2,3,4,5，Yukiko Harima（播磨有希子）¹，Ryoichiro Kageyama（影山龍一郎）^1,2,3,5,6 ¹京都大学 ²京都大学大学院生命科学研究科 ³京都大学大学院生命科学研究科附属生命動態研究センター ⁴科学技術振興機構さきがけ ⁵京都大学物質－細胞統合システム拠点 ⁶京都大学大学院医学研究科 Somatic stem/progenitor cells actively divide and give rise to many mature cells in embryonic tissues, whereas they are usually dormant/quiescent in many adult tissues. The detailed mechanisms that regulate active versus quiescent stem cell states are largely unknown. In active neural stem cells, Hes1 expression autonomously oscillates and periodically represses expression of the proneural gene Ascl1, thereby driving Ascl1 oscillations. Our previous study reported that oscillatory Ascl1 expression activates the proliferation of neural stem cells, suggesting that Hes1 and Ascl1 expressions are involved in the mechanism controlling the active versus quiescent state of neural stem cells. Here, we found that in quiescent neural stem cells in the adult mouse brain Hes1 levels are oscillatory, though the peaks and troughs are higher than those in active neural stem cells, causing Ascl1 expression to be continuously suppressed. Inactivation of Hes1 and its related genes up-regulates Ascl1 expression and increases neurogenesis. This causes rapid depletion of neural stem cells and premature termination of neurogenesis. Conversely, sustained Hes1 expression represses Ascl1, inhibits neurogenesis, and maintains quiescent neural stem cells. By contrast, induction of Ascl1 oscillations activates neural stem cells and increases neurogenesis in the adult mouse brain. Thus, Ascl1 oscillations, which normally depend on Hes1 oscillations, regulate the active state, while high Hes1 expression and resultant Ascl1 suppression promote quiescence in neural stem cells.