# Genetic dissection of auditory circuit assembly

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $575,898

## Abstract

Project Summary
Spiral ganglion neurons (SGNs) encode everything an animal hears and send this information to the brain. In
order to achieve rapid and reliable signal transmission, SGNs exhibit a number of specialized properties,
including the ability to respond to glutamate via large, AMPA-receptor rich post-synaptic densities. Although all
SGNs are glutamatergic, differences in the nature of their synapses and their responses to sound indicate that
there are three distinct subtypes. High spontaneous firing rate (SR) SGNs have low thresholds and are likely the
first to respond to sound. Low SR SGNs have higher thresholds and are proposed to improve the ability to detect
sounds in noise; medium SR SGNs fall in between. These physiological differences are accompanied by parallel
changes in the abundance of AMPA receptors and the size of the opposing pre-synaptic ribbon. Low SR SGN
synapses are more vulnerable to the effects of noise exposure, which may be why some people have trouble
understanding what they hear despite normal auditory thresholds. The long term goal of this project is to
understand how SGNs acquire the properties needed for the perception of sound. More immediately, we will
define the intrinsic transcriptional networks that endow SGN subtypes with their distinct properties and functions.
We hypothesize that SGN diversification depends on the combined activities of a pan-SGN Gata3 network and
a subtype-specific program driven by the transcription factor Runx1. Previously, we showed that Gata3
influences multiple features of SGN differentiation, acting in part through the transcription factor Mafb (Lu et al.,
2011; Appler et al., 2013; Yu et al., 2013). In Mafb mutant mice, SGNs do not develop normal post-synaptic
densities. Subsequently, we showed that Type I SGNs fall into three molecular distinct subtypes (Ia, Ib, and Ic)
that match the features of high, medium, and low SR SGNs respectively (Shrestha et al., 2018). New preliminary
studies suggest that diversification among Type I SGNs requires the transcription factor Runx1, which is
restricted to Ib and Ic subtypes by late embryogenesis and then maintained throughout life. Further, Ic SGNs
appear to be lost from Runx1 conditional knock-out (CKO) mice, as indicated by changes in gene expression
and altered ABR responses. Here, we will define the role of Runx1 and its relationship with Gata3. We will
perform a thorough analysis of Runx1CKO mice, examining SGN composition, synaptic heterogeneity, and the
effects on hearing. In parallel, we will use genetic and viral overexpression approaches to learn how Gata3 and
its Maf effectors influence the emergence of subtype identity and synaptic heterogeneity in vivo. Using single
cell and bulk RNA-sequencing, we will define the molecular programs active in developing Ib/c SGNs and test
how these programs are altered by loss of Runx1 or Gata3, as well as how the Maf factors contribute. These
studies will elucidate the molecular programs dr...

## Key facts

- **NIH application ID:** 10130479
- **Project number:** 5R01DC009223-12
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Lisa Goodrich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $575,898
- **Award type:** 5
- **Project period:** 2009-05-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130479

## Citation

> US National Institutes of Health, RePORTER application 10130479, Genetic dissection of auditory circuit assembly (5R01DC009223-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10130479. Licensed CC0.

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