A newly discovered disorder characterized by malabsorptive diarrhea and a lack of intestinal enteroendocrine cells is caused by loss-of-function mutations in NEUROG3.

BETA2/NeuroD1 is a member of the basic helix-loop-helix (bHLH) transcription factor family, which has been shown to play a major role in development of the nervous system and formation of the endocrine system. Gain-of-function studies have indicated that BETA2/NeuroD1 is important for the neurogenesis of Xenopus embryos and several neurogenic cell lines. Disruption of the gene encoding BETA2/NeuroD1 leads to severe abnormalities of the developing mouse central nervous system as well as the peripheral nervous system. The focus of this article is on the recent progress in understanding the role of BETA2/NeuroD1 in the development of the nervous system.

NeuroD/BETA2, a basic helixloop-helix transcription factor, has been shown to play a role in tissue-specific differentiation of pancreatic and enteroendocrine cells. To gain further insight into the function of neuroD/ BETA2 in the nervous system development, we examined the expression pattern of neuroD/ BETA2 during embryonic and postnatal development by using in situ hybridization. Dynamic changes of neuroD/BETA2 expression in the central nervous system were observed during embryogenesis, especially in telencephalon, hippocampus, cerebellum, spinal cord, and olfactory epithelium. Moderate level of expression was also detected in developing pancreas in early embryogenesis. Although the neuroD/BETA2 expression in cerebellum and hippocampus increased over time, expression in cerebral cortex, spinal cord, as well as in fetal pancreas gradually decreased as embryogenesis proceeded. High level of the neuroD/BETA2 expression in developing cerebellum and hippocampus persisted throughout postnatal development and remained at a stable level in the adult brain. Interestingly, neuroD/BETA2 expression was detected not only in postmitotic but also in mitotic cells, as was evident in its expression in external granular layer of cerebellum and granule cells of the dentate gyrus during postnatal development. This observation suggests that neuroD/BETA2 may have a unique role in proliferation, differentiation, or both, of granule cells of cerebellum and dentate gyrus.

BETA2/NeuroD1 has been shown to play a major role in terminal differentiation of the pancreatic and enteroendocrine cells, as well as for the survival of photoreceptors. Here, we report that the loss of BETA2/NeuroD1 affected the cerebellar development with a major reduction of granule cell number. However, there is a differential reduction of granule cells along the anterior and posterior axis of the cerebellum; while the reduction of granule cells in the anterior lobes is substantial, there is an almost complete loss of granule cells in the posterior compartment. To understand the mechanism for this anterior-posterior difference, we carried out detailed analyses. We found that both BETA2/NeuroD1 and its direct target TrkC, expression commence earlier in the posterior part than those in the anterior part during cerebellum development. Consequently, loss of BETA2/NeuroD1 enhances granule cell death in the posterior 2 days earlier than the anterior. Furthermore, the higher rate of cell death in the posterior of the cerebellum is concomitant with the reduction of TrkC expression in knockout mice. Thus, our data indicate that preferential expression of BETA2/NeuroD1 and TrkC in posterior lobes explains the earlier start of cell apoptosis and preferential loss of granule cells in the posterior lobes.

The BETA2/NeuroD1 null mouse has cochlear dysplasia. Its cochlear duct is shorter than normal, there is a lack of spiral ganglion neurons, and there is hair cell disorganization. We measured vertical movements of the tectorial membrane at acoustic frequencies in excised cochleae in response to mechanical stimulation of the stapes using laser doppler vibrometry. While tuning curve sharpness was similar between wild-type, heterozygotes, and null mice in the base, null mutants had broader tuning in the apex. At both the base and the apex, null mice had less phase lag accumulation with increasing stimulus frequency than wild-type or heterozygote mice. In vivo studies demonstrated that the null mouse lacked distortion product otoacoustic emissions, and the cochlear microphonic and endocochlear potential were found to be severely reduced. Electrically evoked otoacoustic emissions could be elicited, although the amplitudes were lower than those of wild-type mice. Cochlear cross-sections revealed an incomplete partition malformation, with fenestrations within the modiolus that connected the cochlear turns. Outer hair cells from null mice demonstrated the normal pattern of prestin expression within their lateral walls and normal FM 1-43 dye entry.Overall, these data demonstrate that while tonotopicity can exist with cochlear dysplasia, traveling wave propagation is abnormally fast. Additionally, the presence of electrically evoked otoacoustic emissions suggests that outer hair cell reverse transduction is present, although the acoustic response is shaped by the alterations in cochlear mechanics.