Hes1 is a negative regulator of inner ear hair cell differentiation

Hair cell fate determination in the inner ear has been shown to be controll ed by specific genes. Recent loss-of-function and gain-of-function experime nts have demonstrated that Math1, a mouse homolog of the Drosophila gene at onal, is essential for the production of hair cells. To identify genes that may interact with Math1 and inhibit hair cell differentiation, we have foc used on Hes1, a mammalian hairy and enhancer of split homolog, which is a n egative regulator of neurogenesis, We report here that targeted deletion of Hes1 leads to formation of supernumerary hair cells in the cochlea and utr icle of the inner ear. RT-PCR analysis shows that Hes1 is expressed in inne r ear during hair cell differentiation and its expression is maintained in adulthood. In situ hybridization with late embryonic inner ear tissue revea ls that Hes1 is expressed in supporting cells, but not hair cells, of the v estibular sensory epithelium. In the cochlea, Hes1 is selectively expressed in the greater epithelial ridge and lesser epithelial ridge regions which are adjacent to inner and outer hair cells. Co-transfection experiments in postnatal rat explant cultures show that overexpression of Heal prevents ha ir cell differentiation induced by Math1. Therefore Hes1 can negatively reg ulate hair cell differentiation by antagonizing Math1. suggest that a balan ce between Math1 ana negative regulators such as Hes1 is crucial for the pr oduction of an appropriate number of inner ear hair cells.