Control of CNS Cell-fate Decisions by SHP-2 and Its Dysregulation in Noonan Syndrome

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2007 Apr 20

PMID 17442246

Citations 82

Authors

Andree S Gauthier

Olivia Furstoss

Toshiyuki Araki

Richard Chan

Benjamin G Neel

David R Kaplan

Freda D Miller

Affiliations

Soon will be listed here.

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.

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