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

Abstract

BETA2/NeuroD is a homologue of the Drosophila atonal gene that is widely expressed during development in the mammalian brain and pancreas. Although studies in Xenopus suggest that BETA2/NeuroD is involved in cellular differentiation, its function in the mammalian nervous system is unclear. Here we show that mutant mice homozygous for a deletion at the BETA2/NeuroD locus fail to develop a granule cell layer within the dentate gyrus, one of the principal structures of the hippocampal formation. To understand the basis of this abnormality, we analyzed dentate gyrus development by using immunocytochemical markers in BETA2/NeuroD -deficient mice. The early cell populations in the dentate gyrus, including Cajal–Retzius cells and radial glia, are present and appear normally organized. The migration of dentate precursor cells and newly born granule cells from the neuroepithelium to the dentate gyrus remains intact. However, there is a dramatic defect in the proliferation of precursor cells once they reach the dentate and a significant delay in the differentiation of granule cells. This leads to malformation of the dentate 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 specific class of neurons. Furthermore, failure to express BETA2/NeuroD leads to a stereotyped pattern of pathological excitability of the adult central nervous system.

Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis

“…To identify potential targets of Wnt signaling within the hippocampal niche, we focused on genes expressed in the adult DG. Prox1 is a prospero-related homeodomain transcription factor, which is highly expressed in DG granule cells (10,15,16). Prox1 has previously been shown to be important for lens development, lymphangiogenesis, differentiation of certain spinal cord interneurons, and, very recently, in hippocampal granule cell genesis (17)(18)(19)(20).…”

“…There, β-catenin acts as a transcriptional coactivator of TCF/LEF transcription factors, resulting in the expression of Wnt target genes. Recently, it has been shown that NeuroD1, a basic helix-loop-helix transcription factor required for granule cell genesis in the embryonic and adult DG, is regulated by β-catenin-dependent signaling (9)(10)(11)(12). However, NeuroD1 is not only important for hippocampal neurogenesis but is also involved in the generation of SVZ-derived olfactory neurons (11,13,14).…”

NeuroD1 induces terminal neuronal differentiation in olfactory neurogenesis

“…Given that NeuroD1 deficiency in mice is generally associated with perinatal lethality (14,15,21), we used a strategy based on RNAi in concert with postnatal in vivo electroporation to knock down NeuroD1 in the olfactory bulb neurogenic system. For validation, three different NeuroD1 specific shRNA vectors were cotransfected with a NeuroD1 expression construct into COS-7 cells.…”

“…To do so we isolated neuronal precursors and differentiated interneurons from the periglomerular lineage of the OB and compared their gene expression by microarray. We established that the expression of NeuroD1, a bHLH transcription factor that has been implicated in neuronal differentiation in several experimental systems (13)(14)(15)(16)(17), coincides with the passage from neuronal precursor to mature interneurons. Functionally, we show that premature expression of NeuroD1 in vitro and in vivo induced highly efficiently the differentiation of forebrain progenitors.…”

Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene

“…NeuroD1 knockout mice display a malformation of the dentate gyrus, one of the principal structures of the hippocampus, and exhibit spontaneous limbic seizures. 23 ATF2 is a leucine zipper transcription factor, which binds to cAMP-response elements (CREs), forming homodimers or heterodimers with c-jun to stimulate CRE-dependent transcription. 24 The protein also has intrinsic histone acetyltransferase activity, which is modulated by phosphorylation, and has been proposed to activate transcription by direct effects on chromatin components.…”