Hedgehog co-receptor Cdo negatively regulates inner ear hair cell specification

Abstract

Hearing loss is one of the most common congenital disorder affecting over 360 million people globally, with approximately 1 in 800 children born with a serious permanent hearing impairment. Although genes involved in deafness have been reported, a large number of human deafness related genes remain to be identified. The development of the inner ear involves complex processes of patterning, morphogenesis and cell fate specification. Cdo (Cell adhesion molecule-related, down-regulated by oncogenes) is novel receptors of the Hedgehog (Hh) pathway. Mutations in Cdo cause holoprosencephaly, a human congenital anomaly defined by forebrain midline defects prominently associated with diminished Hedgehog pathway activity. Cdo functions as both components and targets of the Hh signalling and feedback network. Cdo enhances Shh signalling by acting as co-receptors with Ptch1, or via regulation of Gli transcription factors. A proper balance of Gli repressor and activators is required to mediate Hh signalling druing inner ear morphogenesis. Cdo homozygous knockout mice have profound hearing loss. However, the role of Cdo in inner ear development is still unknown. To understand the function of Cdo co-receptor in the modulation of Hh signaling in mammalian inner ear development, we present the differential expression pattern of Cdo in the developing mouse inner ear and analyse Cdo mouse mutant phenotypes. We found that the expression of Cdo at E12.5 marks the prospective organ of Corti, but by E16 Cdo is down-regulated in cells that will differentiate into hair cells and becomes restricted to supporting cells, suggest that Cdo may have distinct roles in molecular pathways that direct cells towards different cell fates in cochlea. Besides, the otic vesicle-derived inner ear structures are under-developed, with reduced proliferation and premature cell cycle exit during prosensory specification and ectopic hair cells formation in the Cdo mutants. It is possible that Cdo in Hh signaling are required for inhibiting cells from differentiating into hair cells and specifying progenitor cells to generate the distinctly fated cell populations in the inner ear.