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
Share this article
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
  2. Download BibTeX
  3. Download .RIS

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.

Reviewing Editor

  1. Lotte B Pedersen, University of Copenhagen, Denmark

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.

Version history

  1. Received: December 6, 2021
  2. Preprint posted: January 26, 2022 (view preprint)
  3. Accepted: February 7, 2023
  4. Accepted Manuscript published: February 9, 2023 (version 1)
  5. Version of Record published: March 3, 2023 (version 2)

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.

Metrics

  • 921
    views
  • 206
    downloads
  • 2
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  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

Categories and tags

Research organisms

Further reading

    1. Developmental Biology

    Inhibitory G proteins play multiple roles to polarize sensory hair cell morphogenesis

    Amandine Jarysta, Abigail LD Tadenev ... Basile Tarchini
    Research Article

    Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and for hearing. The extent and nature of their actual contributions remains unclear, however, as previous studies did not investigate all GNAI proteins and included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3, and GNAO proteins, but may also induce unrelated defects. Here, we directly and systematically determine the role(s) of each individual GNAI protein in mouse auditory hair cells. GNAI2 and GNAI3 are similarly polarized at the hair cell apex with their binding partner G protein signaling modulator 2 (GPSM2), whereas GNAI1 and GNAO are not detected. In Gnai3 mutants, GNAI2 progressively fails to fully occupy the sub-cellular compartments where GNAI3 is missing. In contrast, GNAI3 can fully compensate for the loss of GNAI2 and is essential for hair bundle morphogenesis and auditory function. Simultaneous inactivation of Gnai2 and Gnai3 recapitulates for the first time two distinct types of defects only observed so far with pertussis toxin: (1) a delay or failure of the basal body to migrate off-center in prospective hair cells, and (2) a reversal in the orientation of some hair cell types. We conclude that GNAI proteins are critical for hair cells to break planar symmetry and to orient properly before GNAI2/3 regulate hair bundle morphogenesis with GPSM2.

    1. Computational and Systems Biology
    2. Developmental Biology

    A logic-incorporated gene regulatory network deciphers principles in cell fate decisions

    Gang Xue, Xiaoyi Zhang ... Zhiyuan Li
    Research Article

    Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.

    1. Developmental Biology
    2. Evolutionary Biology

    The rapidly evolving X-linked MIR-506 family fine-tunes spermatogenesis to enhance sperm competition

    Zhuqing Wang, Yue Wang ... Wei Yan
    Research Article

    Despite rapid evolution across eutherian mammals, the X-linked MIR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (SLITRK2 and FMR1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked MIR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernible defects, but simultaneous ablation of five clusters containing 19 members of the MIR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility, and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked MIR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the MIR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis.