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Neuron. 2007 Apr 19;54(2):245-62.

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

Author information

1
Developmental Biology Program, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.

Abstract

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 SHP-2 activation may contribute to the cognitive impairments in NS patients.

PMID:
17442246
PMCID:
PMC1900070
DOI:
10.1016/j.neuron.2007.03.027
[Indexed for MEDLINE]
Free PMC Article

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