NeuroD2 is necessary for development and survival of central nervous system neurons

NeuroD2 is sufficient to induce cell cycle arrest and neurogenic differenti ation in nonneuronal cells. To determine whether this bHLH transcription fa ctor was necessary for normal brain development, we used homologous recombi nation to replace the neuroD2 coding region with a p-galactosidase reporter gene. The neuroD2 gene expressed the reporter in a subset of neurons in th e central nervous system, including in neurons of the neocortex and hippoca mpus and cerebellum. NeuroD2(-/-)mice showed normal development until about day P14, when they began exhibiting ataxia and failure to thrive. Brain ar eas that expressed neuroD2 were smaller than normal and showed higher rates of apoptosis, Cerebella of neuroD2-null mice expressed reduced levels of g enes encoding proteins that support cerebellar granule cell survival, inclu ding brain-derived neurotrophic factor (BDNF), Decreased levels of BDNF and higher rates of apoptosis in cerebellar granule cells of neuroDe(-/-)mice indicate that neuroD2 is necessary for the survival of specific populations of central nervous system neurons in addition to its known effects on cell cycle regulation and neuronal differentiation. (C) 2001 Academic Press.