Costello syndrome H-Ras alleles regulate cortical development

Genetic mutations in H-Ras cause Costello syndrome (CS), a complex developmental disorder associated with cortical abnormalities and profound mental retardation. Here, we have asked whether there are perturbations in precursor cell proliferation, differentiation, or survival as a consequence of expressing CS H-Ras alleles that could explain the cognitive deficits seen in this disorder. Two different H-Ras alleles encoding mutations present in CS patients, H-RasG12V and H-RasG12S were expressed in cortical progenitors in culture and in vivo by in utero electroporation and their effects on cortical precursor cell fate examined. Expression of both mutants in cultured precursors inhibited neurogenesis and promoted proliferation and astrogenesis. In vivo, expression of either form of CS H-Ras promoted cell proliferation and inhibited neurogenesis. Moreover, these H-Ras mutants promoted premature gliogenesis, causing formation of astrocytes at a time when normal gliogenesis has not yet begun, ultimately leading to an increase in the number of astrocytes postnatally. Thus, aberrant H-Ras activation enhances neural precursor cell proliferation, and perturbs the normal genesis of neurons and glial cells, effects that likely contribute to the cortical abnormalities and cognitive dysfunction seen in CS.