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

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 Noon...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2007-04, Vol.54 (2), p.245-262
Main Authors: Gauthier, Andrée S., Furstoss, Olivia, Araki, Toshiyuki, Chan, Richard, Neel, Benjamin G., Kaplan, David R., Miller, Freda D.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Astrocytes - physiology
Blotting, Western
Brain research
Cell Proliferation
Cells, Cultured
Central Nervous System - cytology
Central Nervous System - physiology
Cerebral Cortex - cytology
Cerebral Cortex - embryology
Cerebral Cortex - physiology
Electroporation
Evacuations & rescues
Experiments
Extracellular Signal-Regulated MAP Kinases - physiology
Female
HUMDISEASE
Immunohistochemistry
Intracellular Signaling Peptides and Proteins - genetics
Janus Kinases - physiology
Kinases
Mice
MOLNEURO
Neurogenesis
Neuroglia - physiology
Neurons
Neurons - physiology
Noonan Syndrome - physiopathology
Pregnancy
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatases - genetics
Proteins
Rodents
Signal Transduction - physiology
Software
STAT Transcription Factors - physiology
Stem Cells - physiology
STEMCELL
Transfection
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Summary: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.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2007.03.027