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

Neuron. 2007 Apr 19;54(2):245-62. doi: 10.1016/j.neuron.2007.03.027.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / physiology
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Central Nervous System / cytology
  • Central Nervous System / physiology*
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology
  • Cerebral Cortex / physiology
  • Electroporation
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Female
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Janus Kinases / physiology
  • Mice
  • Neuroglia / physiology
  • Neurons / physiology
  • Noonan Syndrome / physiopathology*
  • Pregnancy
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / genetics*
  • STAT Transcription Factors / physiology
  • Signal Transduction / physiology
  • Stem Cells / physiology
  • Transfection


  • Intracellular Signaling Peptides and Proteins
  • STAT Transcription Factors
  • Janus Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse