# Patterning of the Cochlear Apex-to-Base Axis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $477,922

## Abstract

ABSTRACT
Morphogens such as sonic hedgehog and retinoic acid form gradients that pattern the apex-to-base axis of the
mammalian and avian embryonic cochlea, thereby resulting in differential hair cell size and stereociliary
organization. Although much has been learned about how these individual gradients are established, how they
are integrated and translated into region-specific characteristics at the cellular level remains unclear. Therefore,
the objective of this proposal is to define the molecular mechanisms that encode tonotopic identity at the
transcriptional and epigenetic levels. The central hypothesis of this proposal is that hedgehog signaling acts
upstream of a cascade involving retinoic acid, miRNAs, and the chromatin modifier HMGA2, thus imprinting
positional information in the cochlea. To test this hypothesis, three Specific Aims will be pursued. First, the
hypothesis that hedgehog signaling controls retinoic acid signaling activity will be tested by mapping the retinoic
acid signaling activity in hedgehog gain or loss of function experiments. Furthermore, hedgehog effectors (GLI1-
3) will be classified into transcriptional activators and repressors, and GLI target genes will be identified through
a gene regulatory network analysis. Also, genes modulating retinoic acid activity among the hedgehog targets,
such as Cyp26b1, will be identified using a hedgehog loss of function paradigm. Second, the hypothesis that
retinoic acid induces expression of miRNAs, thus shaping opposing mRNA gradients will be tested. Initial
experiments will determine whether let7 is a critical factor in shaping the cochlear Hmga2 gradient by blocking
of specific let7 family members. Next, miRNAs and mRNAs among the retinoic acid regulated genes will be
identified by using a retinoic acid loss of function allele. Third, the hypothesis that HMGA2 controls tonotopic
maturation of postnatal HCs will be tested. Initially, the temporal requirement for Hmga2 in hearing acquisition
will be determined by deletion of Hmga2 before and after the onset of hearing. Cell type specific functions for
Hmga2 will be elucidated by characterizing hearing and cell type specific markers upon conditional loss of Hmga2
in prosensory progenitors and hair cells. Finally, the impact of HMGA2 on the chromatin landscape will be
determined upon conditional deletion of Hmga2. Our expected outcomes after successful completion of the
proposed project include comprehensive characterization of the gene regulatory network mediating apex-to-base
patterning in the cochlea. The results should explain the transcriptional and epigenetic mechanisms guiding
tonotopic development in the auditory periphery. Learning how the auditory sensor is constructed will be critical
to enable future studies, including those aimed at regenerating lost hearing.

## Key facts

- **NIH application ID:** 10857417
- **Project number:** 1R01DC021687-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Joerg Waldhaus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $477,922
- **Award type:** 1
- **Project period:** 2024-02-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857417

## Citation

> US National Institutes of Health, RePORTER application 10857417, Patterning of the Cochlear Apex-to-Base Axis (1R01DC021687-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10857417. Licensed CC0.

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