Yamamoto S, Yoshino I, Shimazaki T, Murohashi M, Hevner R F, Lax I, Okano H, Shibuya M, Schlessinger J, Gotoh N
Division of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15983-8. doi: 10.1073/pnas.0507961102. Epub 2005 Oct 20.
Mammalian corticogenesis occurs through a complex process that includes neurogenesis, in which neural progenitor cells proliferate, differentiate, and migrate. It has been reported recently that neurogenesis occurs in the subventricular zone (SVZ), a region previously thought to be the primary site of gliogenesis. It has been recognized that in the SVZ, intermediate progenitor cells, derived from radial glial cells that are multipotent neural stem cells, produce only neurons. However, the molecular mechanisms underlying the regulation of neural stem cells and intermediate progenitor cells as well as their contribution to overall corticogenesis remain unknown. The docking protein FRS2alpha is a major mediator of signaling by means of FGFs and neurotrophins. FRS2alpha mediates many of its pleiotropic cellular responses by recruiting the adaptor protein Grb2 and the protein tyrosine phosphatase Shp2 upon ligand stimulation. Here, we report that targeted disruption of Shp2-binding sites in FRS2alpha leads to severe impairment in cerebral cortex development in mutant mice. The defect in corticogenesis appears to be due at least in part to abnormalities in intermediate progenitor cells. Genetic evidence is provided that FRS2alpha plays critical roles in the maintenance of intermediate progenitor cells and in neurogenesis in the cerebral cortex. Moreover, FGF2-responsive neurospheres, which are cell aggregates derived from neural stem/progenitor cells (NSPCs), from FRS2alpha mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2alpha play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.
哺乳动物的皮质发生是一个复杂的过程，包括神经发生，即神经祖细胞增殖、分化和迁移。最近有报道称，神经发生发生在脑室下区（SVZ），该区域以前被认为是胶质发生的主要部位。人们已经认识到，在SVZ中，源自多能神经干细胞即放射状胶质细胞的中间祖细胞仅产生神经元。然而，神经干细胞和中间祖细胞调控的分子机制及其对整体皮质发生的贡献仍然未知。对接蛋白FRS2α是成纤维细胞生长因子（FGFs）和神经营养因子信号传导的主要介质。FRS2α在配体刺激后通过募集衔接蛋白Grb2和蛋白酪氨酸磷酸酶Shp2介导其许多多效性细胞反应。在此，我们报告FRS2α中Shp2结合位点的靶向破坏导致突变小鼠大脑皮质发育严重受损。皮质发生缺陷似乎至少部分归因于中间祖细胞的异常。提供了遗传证据，表明FRS2α在维持中间祖细胞和大脑皮质神经发生中起关键作用。此外，来自FRS2α突变小鼠的FGF2反应性神经球（源自神经干细胞/祖细胞（NSPCs）的细胞聚集体）比野生型小鼠的小。然而，突变的NSPCs能够自我更新，表明FRS2α上Shp2结合位点在NSPC增殖中起重要作用，但在FGF2刺激后对NSPC自我更新能力是可有可无的。
