Dysregulation of sonic hedgehog signaling causes hearing loss in ciliopathy mouse models
Abstract
Defective primary cilia cause a range of diseases known as ciliopathies, including hearing loss. The etiology of hearing loss in ciliopathies, however, remains unclear. We analyzed cochleae from three ciliopathy mouse models exhibiting different ciliogenesis defects: Intraflagellar transport 88 (Ift88), Tbc1d32 (a.k.a. bromi), and Cilk1 (a.k.a. Ick) mutants. These mutants showed multiple developmental defects including shortened cochlear duct and abnormal apical patterning of the organ of Corti. Although ciliogenic defects in cochlear hair cells such as misalignment of the kinocilium are often associated with the planar cell polarity pathway, our results showed that inner ear defects in these mutants are primarily due to loss of sonic hedgehog signaling. Furthermore, an inner ear-specific deletion of Cilk1 elicits low-frequency hearing loss attributable to cellular changes in apical cochlear identity that is dedicated to low-frequency sound detection. This type of hearing loss may account for hearing deficits in some patients with ciliopathies.
Data availability
All data generated or analysed during this study are included in the manuscript. Source data files have been provided for all the data that are represented as graphs in Figures.
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Funding
National Research Foundation of Korea (NRF-2014M3A9D5A01073865)
- Jinwoong Bok
National Research Foundation of Korea (NRF-2016R1A5A2008630)
- Jinwoong Bok
National Research Foundation of Korea (NRF-2017R1A2B3009133)
- Jinwoong Bok
National Research Foundation of Korea (NRF-2014M3A9D5A01073969)
- Hyuk Wan Ko
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal protocols were approved by the Institutional Animal Care and Use Committee (IACUC) at Yonsei University College of Medicine with NIH guidelines (No. 2018-0023).
Copyright
© 2020, Moon et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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