1. Developmental Biology

Absence of CEP78 causes photoreceptor and sperm flagella impairments in mice and a human individual

  1. Tianyu Zhu
  2. Yuxin Zhang
  3. Xunlun Sheng
  4. Xiangzheng Zhang
  5. Yu Chen
  6. Hongjing Zhu
  7. Yueshuai Guo
  8. Yaling Qi
  9. Yichen Zhao
  10. Qi Zhou
  11. Xue Chen  Is a corresponding author
  12. Xuejiang Guo  Is a corresponding author
  13. Chen Zhao  Is a corresponding author
  1. Nanjing Medical University, China
  2. Fudan University, China
  3. Gansu Aier Ophthalmiology and Optometry Hospital, China
  4. The First Affiliated Hospital of Nanjing Medical University, China
https://doi.org/10.7554/eLife.76157
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Cite this article
  1. Tianyu Zhu
  2. Yuxin Zhang
  3. Xunlun Sheng
  4. Xiangzheng Zhang
  5. Yu Chen
  6. Hongjing Zhu
  7. Yueshuai Guo
  8. Yaling Qi
  9. Yichen Zhao
  10. Qi Zhou
  11. Xue Chen
  12. Xuejiang Guo
  13. Chen Zhao
(2023)
Absence of CEP78 causes photoreceptor and sperm flagella impairments in mice and a human individual
eLife 12:e76157.
https://doi.org/10.7554/eLife.76157
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Abstract

Cone rod dystrophy (CRD) is a genetically inherited retinal disease that can be associated with male infertility, while the specific genetic mechanisms are not well known. Here we report CEP78 as a causative gene of a particular syndrome including CRD and male infertility with multiple morphological abnormalities of sperm flagella (MMAF) both in human and mouse. Cep78 knockout mice exhibited impaired function and morphology of photoreceptors, typified by reduced electroretinogram amplitudes, disrupted translocation of cone arrestin, attenuated and disorganized photoreceptor outer segments (OS) disks and widen OS bases, as well as interrupted connecting cilia elongation and abnormal structures. Cep78 deletion also caused male infertility and MMAF, with disordered '9 + 2' structure and triplet microtubules in sperm flagella. Intraflagellar transport (IFT) proteins IFT20 and TTC21A are identified as interacting proteins of CEP78. Furthermore, CEP78 regulated the interaction, stability, and centriolar localization of its interacting protein. Insufficiency of CEP78 or its interacting protein causes abnormal centriole elongation and cilia shortening. Absence of CEP78 protein in human caused similar phenotypes in vision and MMAF as Cep78-/- mice. Collectively, our study supports the important roles of CEP78 defects in centriole and ciliary dysfunctions and molecular pathogenesis of such multi-system syndrome.

Data availability

All H&E, PAS, immunofluorescence, TEM, SEM, uncropped gels and blots, and statistical data are available at corresponding source data files. All mass spectrometry data are available at Dryad deposit:Data of IP-MS was submitted to Dryad (Zhu, Tianyu et al. (2021), Anti-Cep78 immunoprecipitation (IP) coupled with quantitative MS (IP-MS) on testicular lysates of Cep78+/- and Cep78-/- mice, Dryad, Dataset).Data of quantitative MS on elongating spermatids lysates was submitted to Dryad (Dataset, Zhu, Tianyu et al. (2021), Quantitative mass spectrometry (MS) on elongating spermatids lysates of Cep78+/- and Cep78-/- mice, Dryad, Dataset).

The following data sets were generated

Article and author information

Author details

  1. Tianyu Zhu

    Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Yuxin Zhang

    Department of Ophthalmology and Vision Science, Fudan University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Xunlun Sheng

    Gansu Aier Ophthalmiology and Optometry Hospital, Lanzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Xiangzheng Zhang

    Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Yu Chen

    Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Hongjing Zhu

    Department of Ophthalmology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Yueshuai Guo

    Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Yaling Qi

    Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2940-4733

  9. Yichen Zhao

    Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.

  10. Qi Zhou

    Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.

  11. Xue Chen

    Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    For correspondence
    drcx1990@vip.163.com
    Competing interests
    The authors declare that no competing interests exist.

  12. Xuejiang Guo

    Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    For correspondence
    guo_xuejiang@njmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0475-5705

  13. Chen Zhao

    Department of Ophthalmology and Vision Science, Fudan University, Shanghai, China
    For correspondence
    dr_zhaochen@163.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1373-7637

Funding

National Key Research and Development Program of China (2021YFC2700200)

  • Xuejiang Guo

Shanghai Outstanding Academic Leaders (2017BR013)

  • Chen Zhao

Six Talent Peaks Project in Jiangsu Province (YY-019)

  • Xuejiang Guo

Basic Research Program of Jiangsu Province (BK20220316)

  • Tianyu Zhu

Scientific Research Project of Gusu School of Nanjing Medical University (GSBSHKY20213)

  • Tianyu Zhu

National Natural Science Foundation of China (82020108006)

  • Chen Zhao

National Natural Science Foundation of China (81730025)

  • Chen Zhao

National Natural Science Foundation of China (81971439)

  • Xuejiang Guo

National Natural Science Foundation of China (81771641)

  • Xuejiang Guo

National Natural Science Foundation of China (82070974)

  • Xue Chen

National Natural Science Foundation of China (82060183)

  • Xunlun Sheng

National Natural Science Foundation of China (82201764)

  • Tianyu Zhu

China Postdoctoral Science Foundation (2022M711676)

  • Tianyu Zhu

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 mice were raised in a specific-pathogen-free animal facility accredited by Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) in Model Animal Research Center, Nanjing University, China. The facility provided ultraviolet sterilization, a 12-hour light/dark cycle, ad libitum access to water, and standard mouse chow diet. Mice experiments were performed in accordance with approval of the Institutional Animal Care and Use Committee of Nanjing Medical University (IACUC-1707017-8) and with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Human subjects: Our study, conformed to the Declaration of Helsinki, was prospectively reviewed, and approved by the ethics committee of People's Hospital of Ningxia Hui Autonomous Region ([2016] Ethic Review [Scientific Research] NO. 018) and Nanjing Medical University (NMU Ethic Review NO. (2019) 916). Signed informed consents were obtained from all individuals in the study.

Copyright

© 2023, Zhu 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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  1. Tianyu Zhu
  2. Yuxin Zhang
  3. Xunlun Sheng
  4. Xiangzheng Zhang
  5. Yu Chen
  6. Hongjing Zhu
  7. Yueshuai Guo
  8. Yaling Qi
  9. Yichen Zhao
  10. Qi Zhou
  11. Xue Chen
  12. Xuejiang Guo
  13. Chen Zhao
(2023)
Absence of CEP78 causes photoreceptor and sperm flagella impairments in mice and a human individual
eLife 12:e76157.
https://doi.org/10.7554/eLife.76157

Share this article

https://doi.org/10.7554/eLife.76157

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