TY - JOUR
T1 - Follistatin regulates the specification of the apical cochlea responsible for low-frequency hearing in mammals
AU - Koo, Hei Yeun
AU - Kim, Min A.
AU - Min, Hyehyun
AU - Hwang, Jae Yeon
AU - Prajapati-DiNubila, Meenakshi
AU - Kim, Kwan Soo
AU - Matzuk, Martin M.
AU - Park, Juw Won
AU - Doetzlhofer, Angelika
AU - Kim, Un Kyung
AU - Bok, Jinwoong
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Doris Wu for her critical reading of the manuscript, Drs. Jeong-Oh Shin, Ji-Hyun Ma, and Harinarayana Ankamreddy for their help beginning this study, and Mr. Dong-Su Jang (Medical Illustration & Design), part of the Medical Research Support Services group of Yonsei University College of Medicine, for artistic support. This work was supported by the National Research Foundation of Korea (NRF-2014M3A9D5A01073865, NRF-2016R1A5A2008630, and NRF-2022R1A2C3007281 to J.B.; NRF-2022M3E5F2017487 to U.-K.K.), Samsung Science and Technology Foundation (SSTF-BA2101-11 to J.B.), Team Science Award of Yonsei University College of Medicine (6–2021–0004 to J.B.), and
Publisher Copyright:
© 2022 the Author(s).
PY - 2023/1/3
Y1 - 2023/1/3
N2 - 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.
AB - 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.
KW - cochlea
KW - follistatin
KW - frequency discrimination
KW - tonotopy
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U2 - 10.1073/pnas.2213099120
DO - 10.1073/pnas.2213099120
M3 - Article
C2 - 36577057
AN - SCOPUS:85145103610
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
M1 - e2213099120
ER -