The role of Six1 in controlling the microtubule polymerization during inner ear hair cell bundle formation

Professor Sham Mai Har   (Co-Investigator)

18

2015-01-01

2016-06-30

70800

The role of Six1 in controlling the microtubule polymerization during inner ear hair cell bundle formation

ciliogenesis, G-protein, kinocilium, microtubule, Rac1, Six1

Developmental Biology,Growth and Development

201411159187

Seed Fund for PI Research – Basic Research

2014

Completed

Progressive hearing loss is a common disease, with 10% of all ages and 60% of those over 65 years old have debilitating hearing loss with degenerating hair cells. Although genes involved in progressive hearing loss have been reported, a large number of human progressive hearing loss related genes remained to be identified. Haploinsufficiency for Six1 causes branchio-oto-renal syndrome which have been associated with Progressive hearing loss. Inactivation of Six1 in mice results in early arrest of inner ear development at the otic vesicle stage. However, the roles of Six1 in hair cell development at later stages are still unknown. In this project, we conditionally knockout Six1 in hair cells at E15.5 when the cilium starts to migrate. Migration of the kinocilium and hair bundle orientation and shape in cochlear hair cells were affected in Six1cko mutants similar to the reported Rac1cko, Cdc42cko and Gαi3 mutants in G-protein signaling pathway. Based on our initial observations, we hypothesize that Six1 is required in cilium migration and microtubule polymerization for hair bundle formation. In this project, we propose to investigate the interactions between Six1 and Rac1 related G-protein coupled signaling pathway in microtubule polymerization and kinocilium growth. This study will provide new understanding of Six1 function in mammalian cochlear hair bundle development and lead to the discovery of novel functions of Six1 as underlying mechanisms of human progressive hearing loss and new treatments for human deafness.