Analysis of the tissue and temporal specific role of Eya1 in ear development and its contribution to hearing loss

Hearing as one of the five human senses is important not only for communication but also for our quality of life and integration into society, impacting on speech and language skills. Almost 11 million people in the UK (1 in 6 of the population) suffer from deafness or experience significant hearing difficulty, with 45,000 children and young people with permanent deafness. We are able to hear due the unique and complex hearing organ that is the ear. The ear is divided into three parts, the external ear (pinna and ear canal), middle ear, with its three little bones, and inner ear, where the hair cells sense vibrations and transfer information to the brain. The gene Eya1 plays an important role in each of these three part of the ear and patients with mutations in this gene are born with severe hearing problems. Mice with mutations in the same gene are also deaf and are excellent models for learning about the mechanisms behind deafness. This proposal is to examine the role of Eya1 in each of the different parts of the ear using a conditional knockout to control when and where the Eya1 gene is lost. Such analysis will provide important information, not only on the many roles of Eya1 in the ear, but also on how the different tissues of the ear come together and influence each other. Such research will be valuable when examining patients with ear defects, particularly in assessing the consequence of defects in specific components of the ear on hearing.

This project involves use of a conditional Eya1 mouse to follow the role of this gene in specific compartments of the ear during development. Eya1 has a complex expression pattern spanning the whole of embryonic ear development, from E9.5 to postnatal stages with expression in the endoderm, ectoderm, neural crest and mesoderm of the craniofacial region. Using different Cre drivers we can address key questions regarding the role of Eya1 at different time points and in different tissues. In this proposal we will concentrate on the role of Eya1 in the neural crest (Wnt1cre), the endoderm (Sox17 -2a-icre), and the mesoderm (Mesp1cre), and use the PCagErt2cre line to investigate the relative role of Eya1 during key stages of ear development, from the formation of the otic vesicle and the pharyngeal arches to the cavitation of the middle ear at birth. Together this will allow us to dissect out the role of Eya1 and provide an understanding of the defect observed in patients with Eya1 mutations.