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 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.
Gauthier
Andrée S
AS
Developmental Biology Program, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
Furstoss
Olivia
O
Araki
Toshiyuki
T
Chan
Richard
R
Neel
Benjamin G
BG
Kaplan
David R
DR
Miller
Freda D
FD
D000818:Animals; D001253:Astrocytes / Q000502:physiology; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000502:physiology; D018274:Electroporation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D053612:Janus Kinases / Q000502:physiology; D051379:Mice; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009634:Noonan Syndrome / Q000503:physiopathology*; D011247:Pregnancy; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000502:physiology; D014162:Transfection
D047908:Intracellular Signaling Peptides and Proteins; D050791:STAT Transcription Factors; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse