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幹細胞、ニューロンとグリアの分化 1
Stem Cells, Neuronal and Glial Production/Differentiation 1

開催日 2014/9/11
時間 17:00 - 18:15
会場 Room J(313+314)
Chairperson(s) 大塚 俊之 / Toshiyuki Ohtsuka (京都大学ウイルス研究所 細胞生物学研究部門 / Department of Cell Biology, Institute for Virus Research, Kyoto University, Japan)
花嶋 かりな / Carina Hanashima (理化学研究所 発生・再生科学総合研究センター / RIKEN Center for Developmental Biology, Japan)

Mathematical modeling and genetic analysis of the wave of differentiation in the Drosophila visual center

  • O1-J-5-5
  • 佐藤 純 / Makoto Sato:1 三浦 岳 / Takashi Miura:2 長山 雅晴 / Masaharu Nagayama:3 
  • 1:金沢大・脳肝センター / Brain Liver Interface Medicine Research Center, Kanazawa Univ, Japan 2:九大院・医 / Grad Sch Med Sci, Kyushu Univ, Japan 3:北大・電子研 / Res Inst Elect Sci, Hokkaido Univ, Japan 

Notch-mediated lateral inhibition is found in various developmental processes. Here we demonstrate that it plays an unexpected role in combination with EGF signaling in the course of proneural wave progression during development of the Drosophila visual center.
During proneural wave progression, a sheet-like neuroepithelial cells (NE) sequentially differentiate to neuroblasts (NB). Their boundary is defined by the expression of proneural transcription factor family AS-C, which acts as a trigger of differentiation. The wave of differentiation 'proneural wave' sweeps across the NE sheet as AS-C expression progresses. EGF and Notch play a central role in this process by positively and negatively regulating the wave progression, respectively. The ligands of EGF and Notch signalings are specifically expressed in NE immediately prior to NB differentiation. The EGF and Notch signalings not only induce their own ligand expression, but positively regulate each other to form a mutual feedback loop. Since the activity of Notch propagates as a pulse wave without showing a salt-and-pepper pattern, we formulated the proneural wave progression by using a dual reaction-diffusion system of Notch and EGF signalings. Our mathematical model reproduces the elimination and acceleration of the proneural wave observed in EGF and Notch mutant clones, respectively.
Using the above model, we found that the AS-C input to Notch is significantly important to cause the Notch mutant phenotype. In the classical model of lateral inhibition, positive regulation of Notch signaling by AS-C is particularly important. Indeed, our second mathematical model in which the Notch signaling forms the classical lateral inhibitory feedback also reproduces the phenotypes of EGF and Notch mutant clones, suggesting that the Notch signaling can be formulated by either reaction-diffusion or lateral inhibition. Finally, our genetic analysis suggests that the Notch signaling indeed forms a feedback loop of lateral inhibition in vivo. Thus, the combination of the lateral inhibition of Notch and the reaction diffusion of EGF enables the propagation of the wave of differentiation.

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