Professor Matthew Holley has received Rosetrees Trust funding to support a project that involved investigating molecular targets for auditory system regeneration, at Sheffield University. Dr. Tanaya Bardhan also worked on this project, as part of her PhD. They were interested in a signalling pathway influenced by a gene known as gata3, a zinc finger transcription factor which is a key regulator of auditory system development, to further understand the function of GATA3 in cochlear hair cells. For this project, the team used transgenic gata3 mice to determine the role of changing GATA3 expression levels on sensory hair cell development in the inner ear. They also wanted to find out more about specific signalling components, when GATA3 activity is altered.

They have published their findings from the project in The Journal of Physiology. They were able to show that gata3 is crucial for the survival of outer hair cells, as well as for the functional maturation of inner hair cells at the onset of hearing. In the context of work by others these results show that gata3 regulates specific, complementary aspects of development in different cells types to orchestrate the development of the auditory system. In a human condition known as Hypoparathyroidism, Deafness and Renal (HDR) anomaly syndrome, lower levels of gata3 cause severe hearing loss. In subsequent research, Professor Holley’s group has derived reporter cell lines that allow high throughput screening of drugs that can modulate gata3 and potentially compensate for gata3 deficiency. Once characterised, these lines may be of value to other conditions in which gata3 is implicated, for example some forms of cancer and allergic inflammation.

Hearing loss in a transgenic mouse in which gata3 has been deleted only from inner hair cells

Professor Holley said “Gata3 is a fascinating gene because it regulates many different processes in different tissues from the earliest stages of embryonic development through to the adult. Dissecting its function in different cell types allows us to start building a picture of how it coordinates development and how it might be targeted for therapeutic purposes in specific cells.”

Written by: Rebecca Downing and Professor Matthew Holley