Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome

被引:122
作者
Gauthier, Andree S.
Furstoss, Olivia
Araki, Toshiyuki
Chan, Richard
Neel, Benjamin G.
Kaplan, David R.
Miller, Freda D.
机构
[1] Hosp Sick Children, Dev Biol Program, Toronto, ON M5G 1X8, Canada
[2] Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 1X8, Canada
[3] Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5S 1A8, Canada
[4] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada
[5] Harvard Univ, Sch Med, Beth Israel Med Ctr, Dept Med, Boston, MA 02215 USA
关键词
D O I
10.1016/j.neuron.2007.03.027
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:245 / 262
页数:18
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