The mechanosensory hair cell is the linchpin of the auditory and vestibular systems in vertebrates. Hereditary hearing loss (HHL) is a common sensory deficit often linked to defects in the development and/or function of the hair cells. Only one-third of the genes linked to HHL have been identified to date. There is a great need to identify the remainder of the HHL genes, both to understand the molecular genetic basis of hair cell development and function, and to explore ways to mitigate HHL. Preliminary data suggests that clarin-2, a member of the large tetraspanin family of proteins, is an important hair cell gene. Across species, clarin-2 mirrors many of the properties of paralogous protein clarin-1, including similar amino acid sequence, structural organization (motifs) and expression profile in the inner ear. Previous studies show that clarin-1 is an essential hair cell gene and mutation in clarin- 1 results in loss of inner ear function in humans, mice and zebrafish. Based on strong preliminary data, it is hypothesized that clarin-2 is an essential hair cell protein, and loss of clarin-2 will result in loss of hearing and balance in vertebrates. This hypothesis will be tested in the zebrafish model.
Aim 1 : To generate a zebrafish clrn2 knockout model to test the hypothesis that Clrn2 is an essential hair cell protein.
Aim 2 : To determine subcellular localization of zebrafish and human clarin-2 proteins in hair cells. The hair cell phenotype in the clrn2 knockout should be consistent with the localization of the wild-type clarin-2 protein in wild-type hair cells. We anticipate that our findings will reveal novel insights into the clarin-2 mediated mechanisms that regulate the hair cells function, and how loss of clarin-2 causes hearing loss.
Hearing loss is a major health problem; about 13% of Americans ages 12 years or older are affected by bilateral hearing loss. Many forms of hearing loss are of genetic origin and are associated with defects in the mechanosensory hair cells of the inner ear. Understanding the molecular mechanism of hair cell development and function is an important first step to treat the underlying causes of hearing loss. The PI proposes to investigate the role of clarin-2 in hair cells.
