Norrie disease protein is essential for cochlear hair cell maturation.

Abstract

Mutations in the gene for Norrie disease protein (<i>Ndp</i>) cause syndromic deafness and blindness. We show here that cochlear function in an <i>Ndp</i> knockout mouse deteriorated with age: At P3-P4, hair cells (HCs) showed progressive loss of Pou4f3 and Gfi1, key transcription factors for HC maturation, and Myo7a, a specialized myosin required for normal function of HC stereocilia. Loss of expression of these genes correlated to increasing HC loss and profound hearing loss by 2 mo. We show that overexpression of the <i>Ndp</i> gene in neonatal supporting cells or, remarkably, up-regulation of canonical Wnt signaling in HCs rescued HCs and cochlear function. We conclude that Ndp secreted from supporting cells orchestrates a transcriptional network for the maintenance and survival of HCs and that increasing the level of β-catenin, the intracellular effector of Wnt signaling, is sufficient to replace the functional requirement for <i>Ndp</i> in the cochlea.