Citation:
Yushi Hayashi, Hao Chiang, Chunjie Tian, Artur A. Indzhykulian, and Albert S. B. Edge. 2021. “Norrie disease protein is essential for cochlear hair cell maturation.” Proceedings of the National Academy of Sciences, 118, 39.
Abstract:
Norrie disease causes deafness, blindness, and intellectual disability. By analyzing gene expression downstream of Norrie disease protein (Ndp), we show that Ndp controls a network of transcriptional regulators required for maturation and maintenance of cochlear hair cells. We demonstrate that Ndp secretion, after forced expression of the gene in cochlear supporting cells of Ndp-deficient mice, prevents the hearing-loss phenotype exhibited by these mice. Moreover, forced activation of the canonical Wnt pathway mediator, β-catenin, in hair cells is sufficient to rescue hearing, demonstrating that Ndp secreted from supporting cells acts on adjacent hair cells and is required for the maturation and continued functioning of these cells.Mutations in the gene for Norrie disease protein (Ndp) cause syndromic deafness and blindness. We show here that cochlear function in an Ndp 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 Ndp 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 Ndp in the cochlea.All study data are included in the article and/or SI Appendix.
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Last updated on 07/08/2022