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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Astrocytes / physiology
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Blotting, Western
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Cell Proliferation
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Cells, Cultured
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Central Nervous System / cytology
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Central Nervous System / physiology*
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Cerebral Cortex / cytology
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Cerebral Cortex / embryology
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Cerebral Cortex / physiology
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Electroporation
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Extracellular Signal-Regulated MAP Kinases / physiology
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Female
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Immunohistochemistry
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Intracellular Signaling Peptides and Proteins / genetics*
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Janus Kinases / physiology
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Mice
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Neuroglia / physiology
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Neurons / physiology
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Noonan Syndrome / physiopathology*
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Pregnancy
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases / genetics*
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STAT Transcription Factors / physiology
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Signal Transduction / physiology
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Stem Cells / physiology
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Transfection
Substances
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Intracellular Signaling Peptides and Proteins
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STAT Transcription Factors
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Janus Kinases
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Extracellular Signal-Regulated MAP Kinases
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PTPN11 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse