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

• 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
• ISSN: 0896-6273; 1097-4199
• 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.