Sox10 is essential for neural crest invasion in cochleo-vestibular ganglion

Abstract

Background and objectives: Sox10 is a HMG domain transcription factor required for survival of neural crest cells (NCCs) and for gliogenesis in the peripheral nervous system. SOX10 mutations are associated with sensorineural deafness in Waardenburg-Shah syndrome (WS4) patients. In the developing inner ear, Sox10 is expressed in the otic vesicle and the cochleo-vestibular ganglion (CVG). The aim of this study is to investigate the role of Sox10 during CVG development, in order to understand the underlying basis for the hearing defect in WS4.

Methods: To investigate the relationship between NCCs and the developing CVG, we used Wnt1-cre/ZEG and Pax2-cre/ZEG mice to trace the neural crest and otic placode derived cells in CVG respectively. To further investigate the function of Sox10 in the glial lineage, we analysed a mouse mutant Sox10NGFP in which the Sox10 N-terminal domain was fused to EGFP.

Results: Sox10-positive NCCs were first detected in the peripheral region of the geniculate ganglion at early E9.5 in Pax2-cre/ZEG embryos. From 30-somite stage, NCCs colonized the CVG in a discrete pattern, these NCCs then acquired a glial identity, indicating that NCCs invade the CVG and contribute to glial cells. Using the Sox10NGFP mutant, we found that GFP expression persisted in the otic epithelium and glial cells in the spiral ganglion, recapitulating the expression of Sox10 in the inner ear. Sox10NGFP/NGFP mutants lacked NCCs in CVG from E10 onward, but neuronal specification was unaffected, indicating that Sox10 is important for early invasion of NCCs into the CVG. In the absence of glia, spiral ganglion neural fibers displayed disorganized alignment and fasciculation in Sox10NGFP/NGFP mutants at E13.5. Our results indicate that Sox10 expressing glia were essential for radial growth of spiral ganglion neurons.

Conclusions: Taken together, our data demonstrates that Sox10 is required for both early neural crest invasion in the CVG and gliogenesis during inner ear gangliogenesis, and for the normal maintenance of spiral ganglion neurons.