1. Developmental Biology
Download icon

Dysregulation of sonic hedgehog signaling causes hearing loss in ciliopathy mouse models

  1. Kyeong-Hye Moon
  2. Ji-Hyun Ma
  3. Hyehyun Min
  4. Heiyeun Koo
  5. HongKyung Kim
  6. Hyuk Wan Ko  Is a corresponding author
  7. Jinwoong Bok  Is a corresponding author
  1. Yonsei University, Republic of Korea
Research Article
  • Cited 2
  • Views 1,041
  • Annotations
Cite this article as: eLife 2020;9:e56551 doi: 10.7554/eLife.56551

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.

Article and author information

Author details

  1. Kyeong-Hye Moon

    Anatomy, Yonsei University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  2. Ji-Hyun Ma

    Anatomy, Yonsei University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  3. Hyehyun Min

    Anatomy, Yonsei University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  4. Heiyeun Koo

    Anatomy, Yonsei University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  5. HongKyung Kim

    Anatomy, Yonsei University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Hyuk Wan Ko

    Biochemistry, Yonsei University, Seoul, Republic of Korea
    For correspondence
    KOHW@YONSEI.AC.KR
    Competing interests
    The authors declare that no competing interests exist.
  7. Jinwoong Bok

    Anatomy, Yonsei University, Seoul, Republic of Korea
    For correspondence
    bokj@yuhs.ac
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1958-1872

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).

Reviewing Editor

  1. Jeremy F Reiter, University of California, San Francisco, United States

Publication history

  1. Received: March 2, 2020
  2. Accepted: December 31, 2020
  3. Accepted Manuscript published: December 31, 2020 (version 1)
  4. Version of Record published: January 13, 2021 (version 2)

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.

Metrics

  • 1,041
    Page views
  • 191
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Developmental Biology
    2. Evolutionary Biology
    Tom Dierschke et al.
    Research Article

    Eukaryotic life cycles alternate between haploid and diploid phases and in phylogenetically diverse unicellular eukaryotes, expression of paralogous homeodomain genes in gametes primes the haploid-to-diploid transition. In the unicellular Chlorophyte alga Chlamydomonas KNOX and BELL TALE-homeodomain genes mediate this transition. We demonstrate that in the liverwort Marchantia polymorpha paternal (sperm) expression of three of five phylogenetically diverse BELL genes, MpBELL234, and maternal (egg) expression of both MpKNOX1 and MpBELL34 mediate the haploid-to-diploid transition. Loss-of-function alleles of MpKNOX1 result in zygotic arrest, whereas loss of either maternal or paternal MpBELL234 results in variable zygotic and early embryonic arrest. Expression of MpKNOX1 and MpBELL34 during diploid sporophyte development is consistent with a later role for these genes in patterning the sporophyte. These results indicate that the ancestral mechanism to activate diploid gene expression was retained in early diverging land plants and subsequently co-opted during evolution of the diploid sporophyte body.

    1. Developmental Biology
    2. Neuroscience
    Lukas Klimmasch et al.
    Research Article Updated

    The development of binocular vision is an active learning process comprising the development of disparity tuned neurons in visual cortex and the establishment of precise vergence control of the eyes. We present a computational model for the learning and self-calibration of active binocular vision based on the Active Efficient Coding framework, an extension of classic efficient coding ideas to active perception. Under normal rearing conditions with naturalistic input, the model develops disparity tuned neurons and precise vergence control, allowing it to correctly interpret random dot stereograms. Under altered rearing conditions modeled after neurophysiological experiments, the model qualitatively reproduces key experimental findings on changes in binocularity and disparity tuning. Furthermore, the model makes testable predictions regarding how altered rearing conditions impede the learning of precise vergence control. Finally, the model predicts a surprising new effect that impaired vergence control affects the statistics of orientation tuning in visual cortical neurons.