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

Abstract

BETA2/NeuroD1 is a bHLH transcription factor that is expressed during development in the mammalian pancreas and in many locations in the central and peripheral nervous systems. During inner ear ontogenesis, it is present in both sensory ganglion neurons and sensory epithelia. Although studies have shown that BETA2/NeuroD1 is important in the development of the hippocampal dentate gyrus and the cerebellum, its functions in the peripheral nervous system and in particular in the inner ear are unclear. Mice carrying a BETA2/NeuroD1 null mutation exhibit behavioral abnormalities suggestive of an inner ear defect, including lack of responsiveness to sound, hyperactivity, head tilting, and circling. Here we show that these defects can be explained by a severe reduction of sensory neurons in the cochlear-vestibular ganglion (CVG). A developmental study of CVG formation in the null demonstrates that BETA2/NeuroD1 does not play a primary role in the proliferation of neuroblast precursors or in their decision to become neuroblasts. Instead, the reduction in CVG neuron number is caused by a combination both of delayed or 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 in differentiation and patterning of the cochlear duct and sensory epithelium and loss of the dorsal cochlear nucleus. BETA2/NeuroD1 is, thus, the first gene to be shown to regulate neuronal and sensory cell development in both the cochlear and vestibular systems.

Expression of LHX3 and SOX2 during mouse inner ear development

“…Ectopic expression of ATOH1 has been shown to induce the differentiation of hair cells de novo in the embryonic and adult inner ear (Izumikawa et al, 2005;Kawamoto et al, 2003;Woods et al, 2004;Zheng and Gao, 2000). Other members of the bHLH family, including NGN1 and NEUROD2, play a central role in sensoriepithelial and cochleovestibular ganglion development (Kim et al, 2001;Liu et al, 2000;Ma et al, 2000). LHX3 is involved in the differentiation of multiple cell types, including several neuronal subpopulations in the spinal cord and in the pituitary (Hunter and Rhodes, 2005;Shirasaki and Pfaff, 2002).…”

Molecular Genetics of Vestibular Organ Development

“…In addition, ectopic expression of Math1 in rat cochlear cultures resulted in an ectopic appearance of sensory hair cells in nonsensory regions (Zheng and Gao 2000). The onset of Math1 expression in individual sensory organs appears to precede that of Jagged2, consistent with its postulated role as a proneural gene (Shailam et al 1999;Liu et al 2000). However, more recent studies suggest that Math1 functions in hair cell determination rather than specification of the sensory primordium (Chen et al 2002).…”

“…NeuroD is expressed in the presumptive cristae, but the cristae of NeuroD knockout mice appeared normal, even though the number of sensory hair cells in the cochlea is aberrant (Liu et al 2000;Kim et al 2001). In addition, NeuroD is important for the development of the eighth ganglion (see below).…”

“…Two HLH transcription factors, Ngn1 and NeuroD, have been shown to be important for the early phases of ganglion development (Liu et al 2000;Ma et al 2000;Kim et al 2001). NeuroD knockout mice show defects in neuroblast delamination from the otic epithelium and subsequent neuronal differentiation (Liu et al 2000).…”

NeuroD Regulates Neuronal Migration

“…However, the massive cell death of those subsets of neurons due to the absence of NeuroD has prevented the further study of NeuroD in those neurons in later developmental stages. The inner ear vestibular-cochlear ganglia (VCG) cells in NeuroD-deficient mice failed to express normal amounts of the neurotrophin receptors TrkB and TrkC (Kim et al, 2001;Liu et al, 2000), which are essential for the survival and innervation of the VCG neurons. It was followed by the massive cell death of those neurons.…”