Essential role of BETA2/NeuroD1 in development of the vestibular and auditory systems

BETA2/NeuroD1 is a bHLH transcription factor that is expressed during devel opment in the mammalian pancreas and in many locations in the central and p eripheral nervous systems. During inner ear ontogenesis, it is present in b oth sensory ganglion neurons and sensory epithelia. Although studies have s hown that BETA2/NeuroD1 is important in the development of the hippocampal dentate gyrus and the cerebellum, its functions in the peripheral nervous s ystem and in particular in the inner ear are unclear. Mice carrying a BETA2 /NeuroD1 null mutation exhibit behavioral abnormalities suggestive of an in ner ear defect, including lack of responsiveness to sound, hyperactivity, h ead tilting, and circling. Here we show that these defects can be explained by a severe reduction of sensory neurons in the cochlear-vestibular gangli on (CVG). A developmental study of CVG formation in the null demonstrates t hat BETA2/NeuroD1 does not play a primary role in the proliferation of neur oblast precursors or in their decision to become neuroblasts. Instead, the reduction in CVG neuron number is caused by a combination both of delayed o r defective delamination of CVG neuroblast precursors from the otic vesicle epithelium and of enhanced apoptosis both in the otic epithelium and among those neurons that do delaminate to form the CVG. There are also defects i n differentiation and patterning of the cochlear duct and sensory epitheliu m and loss of the dorsal cochlear nucleus. BETA2/NeuroD1 is, thus, the firs t gene to be shown to regulate neuronal and sensory cell development in bot h the cochlear and vestibular systems.