Placode and neural crest origins of congenital deafness in mouse models of Waardenburg-Shah syndrome

Abstract

AbstractMutations in the human genes encoding the endothelin ligand-receptor pairEDN3andEDNRBcause Waardenburg-Shah syndrome (WS4), which includes congenital hearing impairment. The current explanation for auditory dysfunction is a deficiency in migration of neural crest-derived melanocytes to the inner ear. Here, we have explored the role of endothelin signaling in auditory development in mice using neural crest-specific and placode-specificEdnrbmutation. We find a normal representation of neural crest lineage labeled melanocytes in hearing impaired mutant mice. Instead, our results implicate a previously unrecognized role for glial support of synapse assembly between auditory neurons and cochlear hair cells. In addition, placode-specificEdnrbmutation also caused impaired hearing resulting from deficient synaptic transmission. Our observations challenge the current understanding of endothelin signaling in auditory development, invoke independent and separable roles in the neural crest and placodal lineages, and expand the scope of processes that utilize endothelin signaling to create a functional auditory circuitry.