Nearly 120,000 babies born each year in the USA have a structural birth defect, over 30% of whom have abnormalities in craniofacial structure. A majority of craniofacial structural anomalies stem from defects in organs derived from the neural crest and cranial sensory placodes that often result in hearing loss. The Branchio-oto-renal syndrome (BOR) is characterized by craniofacial and otic malformations that include the external, middle, and/or inner ear structures. About 30% of BOS patients also have kidney defects. About half of BOR cases have been genetically diagnosed with mutations in either the transcription factor SIX1 or its cofactor EYA1. However, the role and regulation of Six1 transcriptional activity during different stages of ear morphogenesis is not fully understood. Six1 plays key roles in craniofacial, otic, muscle, and kidney development. A loss in Six1 function has been shown to reduce the expression of several cranial placode genes and cause defects in craniofacial and otic development in zebrafish, Xenopus, chick and mouse models. These experiments have shown that Six1 is differentially regulated during development depending on the cofactors that form a complex with it. Additionally, mutations in known downstream targets of Six1, such as atoh1 and sall1, also cause hearing loss. We propose to investigate the regulation and downstream effects of Six1 transcriptional activity during key steps in inner ear morphogenesis to advance the understanding of the role of Six1 in otic development. We will identify and functionally test proteins that complex with Six1 during key stages of otic development (Aim 1), and genes that require Six1 activity at these developmental stages (Aim 2). The results from the proposed work will uncover new knowledge about Six1-related genes during otic morphogenesis. This novel information will highlight potential gene candidates to improve BOR diagnosis.
Craniofacial anomalies are one of the prevalent forms of birth defects in the US, in many cases, accompanied by hearing loss. One such congenital syndrome is the Branchio-oto-renal syndrome (BOR) in which newborns have craniofacial malformations, hearing loss and, in some cases, kidney defects. This project investigates the role and regulation of Six1 transcriptional activity in ear morphogenesis to identify novel proteins that could serve as potential diagnostic candidates for BOR.