According to the tragedy Oedipus Rex, bad things happen when you run away from fate. During neuronal development, multipotent precursor cells are programmed to differentiate into either neurons or glia. What happens when this program goes awry? Gauthier et al. report that neural cell fate is disrupted in the developmental disorder Noonan syndrome in a recent article in Neuron.
Noonan syndrome causes heart defects, short stature and craniofacial abnormalities. Learning disabilities and mental retardation occur in 25-50% of affected people. In more than 50% of people with Noonan syndrome, the disease maps to a missense mutation in the gene encoding protein-tyrosine phosphatase SHP-2 (PTPN11) that increases phosphatase activity.
In mice, neurogenesis occurs between embryonic days 12 and 17, and astrocyte formation occurs after birth. The authors localized SHP-2 to neuron precursors in the embryonic mouse brain and to differentiated neurons in the postnatal mouse brain. They cultured cortical precursor cells from mice on embryonic day 12. Knockdown of SHP-2 with short hairpin RNA (shRNA) reduced the number of cells positive for the neuron-specific protein 
III-tubulin, suggesting that SHP-2 is important in neuronal differentiation. The cytokine ciliary neurotrophic factor (CNTF) induces astrocyte differentiation. CNTF-treated cultures transfected with SHP-2 shRNA had fewer astrocytes relative to CNTF-treated control cultures, suggesting that SHP-2 inhibits astrocyte development. SHP-2 shRNA did not alter proliferation or apoptosis.
Does SHP-2 affect cell fate? To determine cell lineage, the authors did clonal analysis, plating cortical precursors at low density so they could analyze each precursor's progeny. SHP-2 shRNA reduced the number of neural clones and increased the number of astrocyte clones relative to control, suggesting that SHP-2 directs cortical precursor cells to develop into neurons instead of glia.
An SHP-2 mutation associated with Noonan syndrome encourages neurogenesis and restrains gliogenesis in vivo. Mutant SHP-2 increased the number of neuronal clones and decreased the number of astrocytic clones that developed from transfected cortical precursor cells relative to control. The authors introduced mutant SHP-2 to mouse embryos on embryonic day 14 by electroporation. On embryonic day 18, mice expressing mutant SHP-2 had more neurons in the cortical mantle than did control mice. On postnatal day 3, mice expressing mutant SHP-2 had fewer astrocytes than did control mice.
Unlike most genetic diseases, dominant gain-of-function mutations in SHP-2 cause Noonan syndrome. Mice expressing one mutant copy of SHP-2 are smaller than wild-type littermates and have abnormalities in craniofacial and heart development, consistent with Noonan syndrome. The authors found more neurons and fewer astrocytes in hippocampus and dorsal cortex of Noonan model relative to wild-type mice.
These data suggest that cognitive dysfunction associated with Noonan syndrome may be due to an upset in the balance of neurons and glia in the brain. Perhaps other genetic disorders that cause mental retardation, including Down syndrome and 22q deletion, also alter neuronal cell fate.