Follistatin regulates the specification of the apical cochlea responsible for low-frequency hearing in mammals

Hei Yeun Koo, Min A. Kim, Hyehyun Min, Jae Yeon Hwang, Meenakshi Prajapati-DiNubila, Kwan Soo Kim, Martin M. Matzuk, Juw Won Park, Angelika Doetzlhofer, Un Kyung Kim, Jinwoong Bok

Research output: Contribution to journalArticlepeer-review

Abstract

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in vivo evidence that regional identity in the embryonic cochlea acts as a framework upon which tonotopy-specific properties essential for frequency selectivity in the mature cochlea develop. We found that follistatin (FST) is required for the maintenance of apical cochlear identity, but dispensable for its initial induction. In a fate-mapping analysis, we found that FST promotes expansion of apical cochlear cells, contributing to the formation of the apical cochlear domain. SHH, in contrast, is required both for the induction and maintenance of apical identity. In the absence of FST or SHH, mice produce a short cochlea lacking its apical domain. This results in the loss of apex-specific anatomical and molecular properties and low-frequency-specific hearing loss.

Original languageEnglish (US)
Article numbere2213099120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number1
DOIs
StatePublished - Jan 3 2023

Keywords

  • cochlea
  • follistatin
  • frequency discrimination
  • tonotopy

ASJC Scopus subject areas

  • General

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