Essential role of Shp2-binding sites on FRS2α for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells
Essential role of Shp2-binding sites on FRS2α for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells
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DOI：
10.1073/pnas.0507961102
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发表时间：
2005-11-01
影响因子：
11.1
通讯作者：
Gotoh, N
中科院分区：
文献类型：
--
作者：
Yamamoto, S;Yoshino, I;Gotoh, N
哺乳动物的皮质发生是通过一个复杂的过程发生的，其中包括神经发生，其中神经祖细胞增殖、分化和迁移。最近有报道称，神经发生发生在室下区（SVZ），该区域以前被认为是胶质生成的主要部位。人们已经认识到，在 SVZ 中，源自放射状胶质细胞（多能神经干细胞）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节的分子机制以及它们对整体皮质生成的贡献仍然未知。对接蛋白 FRS2 α 是 FGF 和神经营养素信号传导的主要介质。 FRS2a 通过在配体刺激后招募接头蛋白 Grb2 和蛋白酪氨酸磷酸酶 Shp2 来介导许多多效性细胞反应。在这里，我们报告说，FRS2 α 中的 Shp2 结合位点的靶向破坏会导致突变小鼠大脑皮层发育的严重损害。皮质生成的缺陷似乎至少部分归因于中间祖细胞的异常。遗传证据表明 FRS2 α 在中间祖细胞的维持和大脑皮层神经发生中发挥着关键作用。此外，FRS2 α突变小鼠的 FGF2 反应性神经球（源自神经干/祖细胞 (NSPC) 的细胞聚集体）比 WT 小鼠的小。然而，突变的 NSPC 能够自我更新，这表明 FRS2 α 上的 Shp2 结合位点在 NSPC 增殖中发挥重要作用，但对于 FGF2 刺激后 NSPC 的自我更新能力来说却是可有可无的。
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 FRS2 alpha is a major mediator of signaling by means of FGFs and neurotrophins. FRS2a 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 FRS2 alpha 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 FRS2 alpha 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 FRS2 alpha mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2 alpha play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.