# Role of Fragile X Mental Retardation Protein on Gene Expression in Auditory Brainstem Development

> **NIH NIH K08** · UNIVERSITY OF ROCHESTER · 2022 · $183,679

## Abstract

Fragile X Syndrome (FXS) is the most common heritable autism spectrum disorder and is associated with
auditory features such as hypersensitivity to sound (hyperacusis). FXS is caused by the absence of Fragile X
mental retardation protein (FMRP), which is known to bind specific mRNAs and repress their translation. Little
is known about how FMRP impacts the central auditory pathway. We will study FMRP effects on gene
expression in the auditory brainstem, using the well-established fmr1-knockout (KO) mouse model, which
exhibits auditory hypersensitivity and seizures in response to loud noise. Although the well-established role of
FMRP is translational repression, it has been shown recently in neurons that FMRP can also change the level
of many mRNAs. Whether this occurs in the auditory brainstem is unknown. We have novel transcriptome data
(unpublished) showing that the levels of many mRNAs that are known to be bound by FMRP, and to function in
synaptic pathways, are decreased in the fmr1-KO cochlear nucleus. How this occurs is not known. Aim 1 will
test the hypothesis that direct FMRP binding stabilizes the bound mRNA, but in the absence of FMRP, these
mRNAs have decreased stability (and, therefore, decreased level). We will also determine if decreased
stabilization of mRNA leads to decreased protein level or if it is offset by the loss of FMRP-mediated
translational repression so as to manifest as increased protein level. Another possibility is that FMRP acts
indirectly through translational repression of factors, such nonsense-mediated mRNA decay (NMD) factor,
UPF1. Unpublished data from my research mentor’s lab has shown that induced pluripotent stem cells derived
from FXS-patient fibroblasts manifest an abnormally high level of UPF1 (whose mRNA is bound by FMRP),
resulting in hyperactivated NMD and, as a consequence, reduced levels of cellular NMD target mRNAs. Based
on these data, Aim 2 will test the hypothesis that NMD is hyperactivated in fmr1-KO cochlear nucleus, leading
to gene downregulation. Lastly, it is known that FMRP is involved in activity dependent processes. For
example, dendritic localization of FMRP is increased with glutamatergic signaling and loss of afferent activity
can blunt translational repression by FMRP. Aim 3 will test the hypothesis that the FMRP effects on gene
expression are dependent on afferent activity. We will examine an inducible deafness mouse model to
determine if it can phenocopy the fmr1-KO, indicating that afferent activity is required for FMRP function. The
PI has extensive molecular biology experience, and with the guidance of a primary mentor who is a respected
RNA biologist. The PI will master current RNA techniques and work towards becoming an independent
investigator. Results will reveal how FMRP regulates genes important for auditory development and plasticity.
The ultimate goal is to reveal potential therapeutic targets to treat auditory hypersensitivity and processing
disorders. The mechanism lead...

## Key facts

- **NIH application ID:** 10350694
- **Project number:** 5K08DC019416-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** HITOMI SAKANO
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $183,679
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10350694

## Citation

> US National Institutes of Health, RePORTER application 10350694, Role of Fragile X Mental Retardation Protein on Gene Expression in Auditory Brainstem Development (5K08DC019416-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10350694. Licensed CC0.

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