Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy

BETA2/NeuroD is a homologue of the Drosophila atonal gene that is widely ex pressed during development in the mammalian brain and pancreas. Although st udies in Xenopus suggest that BETA2/NeuroD is involved in cellular differen tiation, its function in the mammalian nervous system is unclear. Here we s how that mutant mice homozygous for a deletion at the BETA2/NeuroD locus fa il to develop a granule cell layer within the dentate gyrus, one of the pri ncipal structures of the hippocampal formation. To understand the basis of this abnormality, we analyzed dentate gyrus development by using immunocyto chemical markers in BETA2/NeuroD-deficient mice. The early cell populations in the dentate gyrus, including Cajal-Retzius cells and radial glia, are p resent and appear normally organized. The migration of dentate precursor ce lls and newly born granule cells from the neuroepithelium to the dentate gy rus remains intact. However, there is a dramatic defect in the proliferatio n of precursor cells once they reach the dentate and a significant delay in the differentiation of granule cells. This leads to malformation of the de ntate granule cell layer and excess cell death. BETA2/NeuroD null mice also exhibit spontaneous limbic: seizures associated with electrophysiological evidence of seizure activity in the hippocampus and cortex. These findings thus establish a critical role of BETA2/NeuroD in the development of a spec ific class of neurons. Furthermore, failure to express BETA2/NeuroD leads t o a stereotyped pattern of pathological excitability of the adult central n ervous system.