We have addressed the role of the proneural bHLH genes Neurogenin2 (Ngn2) a
nd Mash1 in the selection of neuronal and glial fates by neural stem cells.
We show that mice mutant for both genes present severe defects in developm
ent of the cerebral cortex, including a reduction of neurogenesis and a pre
mature and excessive generation of astrocytic precursors. An analysis of wi
ld-type and mutant cortical progenitors in culture showed that a large frac
tion of Ngn2; Mash1 double-mutant progenitors failed to adopt a neuronal fa
te, instead remaining pluripotent or entering an astrocytic differentiation
pathway. Together, these results demonstrate that proneural genes are invo
lved in lineage restriction of cortical progenitors, promoting the acquisit
ion of the neuronal fate and inhibiting the astrocytic fate.