Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome
Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome
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DOI：
10.1016/j.neuron.2007.03.027
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发表时间：
2007-04-19
期刊：
影响因子：
16.2
通讯作者：
Miller, Freda D.
中科院分区：
文献类型：
--
作者：
Gauthier, Andree S.;Furstoss, Olivia;Miller, Freda D.
在发育中的哺乳动物中枢神经系统中，生长因子指导多能前体细胞生成神经元与神经胶质细胞，这一过程如果受到干扰可能会导致神经功能障碍。在这方面，导致蛋白质酪氨酸磷酸酶 SHP-2 组成型激活的基因突变会导致努南综合症 (NS)，该综合症与学习障碍和智力低下有关。在这里，我们证明，在培养的皮质前体或胚胎皮质中基因敲低 SHP-2 可抑制基底神经发生，并导致星形胶质细胞形成增强和早熟。相反，NS SHP-2 突变体的表达促进神经发生并抑制星形细胞发生。在模仿人类 NS 表型的小鼠基因敲入模型中，神经细胞的命运决定也受到类似的干扰。因此，SHP-2 在神经发生期指示前体细胞产生神经元而不是星形胶质细胞，并且在 SHIP-2 组成型激活后这两种细胞类型的相对比例的扰动可能导致 NS 患者的认知障碍。
Within the developing mammalian CNS, growth factors direct multipotent precursors to generate neurons versus glia, a process that if perturbed might lead to neural dysfunction. In this regard, genetic mutations resulting in constitutive activation of the protein tyrosine phosphatase SHP-2 cause Noonan Syndrome (NS), which is associated with learning disabilities and mental retardation. Here, we demonstrate that genetic knockdown of SHP-2 in cultured cortical precursors or in the embryonic cortex inhibited basal neurogenesis and caused enhanced and precocious astrocyte formation. Conversely, expression of an NS SHP-2 mutant promoted neurogenesis and inhibited astrogenesis. Neural cell-fate decisions were similarly perturbed in a mouse knockin model that phenocopies human NS. Thus, SHP-2 instructs precursors to make neurons and not astrocytes during the neurogenic period, and perturbations in the relative ratios of these two cell types upon constitutive SHIP-2 activation may contribute to the cognitive impairments in NS patients.