Spiral ganglion neurons (SGNs) transmit all auditory information from the cochlea to the brain. When SGNs are missing or dysfunctional, hearing is impaired. Conversely, stimulation of SGNs by cochlear implants offers an effective treatment for deafness. Unfortunately, SGNs are a primary cellular target for deafness caused by inherited mutations, ototoxicity, aging, and noise. Indeed, one of the earliest effects of acoustic overexposure in animal models is loss of the synapses between hair cells and SGNs, followed by withdrawal of the SGN terminals. SGNs subsequently undergo a slow degeneration that interferes with normal hearing, sometimes years after the original injury. Identifying ways to preserve SGNs and their contacts is therefore a priority in auditory neuroscience. An exciting approach for the treatment of deafness is to harness the power of key regulatory molecules that direct circuit assembly during development in order to recapitulate these events in the damaged cochlea. Towards this end, we have identified the transcription factor Gata3 as a potent regulator of SGN development. Gata3 acts repeatedly during auditory circuit assembly, first to direct SGN production and subsequently to coordinate multiple facets of SGN differentiation. In the immune system, Gata3 cooperates with Maf family members to drive terminal differentiation and the acquisition of cell-type specific properties. Similarly, we found that the Maf family member MafB acts downstream of Gata3 to control the formation of synapses between SGNs and hair cells. Intriguingly, Gata3 is also required for expression of a second family member, c- Maf, which is expressed with MafB in differentiating SGNs. Based on these observations, we hypothesize that Gata3 is at the center of a transcriptional network that guides SGN development and differentiation, acting in part through Maf effectors. We will test this hypothesis by performing three lines of investigation. 1) We will create and analyze new lines of Gata3 conditional knock-out mice in order to determine whether Gata3 is specifically required for SGN maturation and survival after the onset of MafB expression. 2) Through analysis of c-Maf conditional knock-out and conditional expressor mice, we will uncover the role of c-Maf during SGN differentiation, focusing on a potential role in the emergence of appropriate firing properties. 3) We will elucidate molecular interactions within the Gata3 network by defining target genes for Gata3, MafB, and c-Maf in SGNs. Results from these experiments will provide important insights into how SGNs acquire their unique features and will establish new molecular entry points for the treatment of diverse forms of hearing loss. In addition, our work will shed light on the etiology of deafness associated with hypoparathyroidism, sensorineural deafness, and renal anomalies (HDR), which is caused by mutations in GATA3 in humans.

Public Health Relevance

The sense of hearing depends on the activity of neurons in the inner ear, which respond to sound stimuli and transmit this information quickly and reliably to the brain. These neurons are highly vulnerable to injury, especially in response to loud noises. By finding the molecules that determine how auditory neurons acquire their specialized properties during development, we will identify new ways to protect and repair the inner ear and thereby prevent hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009223-07
Application #
9035373
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Freeman, Nancy
Project Start
2007-12-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
Shrestha, Brikha R; Chia, Chester; Wu, Lorna et al. (2018) Sensory Neuron Diversity in the Inner Ear Is Shaped by Activity. Cell 174:1229-1246.e17
Druckenbrod, Noah R; Goodrich, Lisa V (2015) Sequential Retraction Segregates SGN Processes during Target Selection in the Cochlea. J Neurosci 35:16221-35
Lu, Cindy C; Cao, Xiao-Jie; Wright, Samantha et al. (2014) Mutation of Npr2 leads to blurred tonotopic organization of central auditory circuits in mice. PLoS Genet 10:e1004823
Yu, Wei-Ming; Goodrich, Lisa V (2014) Morphological and physiological development of auditory synapses. Hear Res 311:3-16
Yu, Wei-Ming; Appler, Jessica M; Kim, Ye-Hyun et al. (2013) A Gata3-Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing. Elife 2:e01341
Appler, Jessica M; Lu, Cindy C; Druckenbrod, Noah R et al. (2013) Gata3 is a critical regulator of cochlear wiring. J Neurosci 33:3679-91
Lu, Cindy C; Appler, Jessica M; Houseman, E Andres et al. (2011) Developmental profiling of spiral ganglion neurons reveals insights into auditory circuit assembly. J Neurosci 31:10903-18
Appler, Jessica M; Goodrich, Lisa V (2011) Connecting the ear to the brain: Molecular mechanisms of auditory circuit assembly. Prog Neurobiol 93:488-508