Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling

  1. Gang Zhai
  2. Tingting Shu
  3. Guangqing Yu
  4. Haipei Tang
  5. Chuang Shi
  6. Jingyi Jia
  7. Qiyong Lou
  8. Xiangyan Dai
  9. Xia Jin
  10. Jiangyan He
  11. Wuhan Xiao
  12. Xiaochun Liu
  13. Zhan Yin  Is a corresponding author
  1. Chinese Academy of Sciences, China
  2. Sun Yat-sen University, China
  3. Institute of hydrobiology, Chinese academy of sciences, China
  4. Huazhong Agriculture University, China
  5. Southwest University, China

Abstract

Disruption of androgen signaling is known to cause testicular malformation and defective spermatogenesis in zebrafish. However, knockout of cyp17a1, a key enzyme responsible for the androgen synthesis, in ar-/- male zebrafish paradoxically causes testicular hypertrophy and enhanced spermatogenesis. Because Cyp17a1 plays key roles in hydroxylation of pregnenolone and progesterone (P4), and convert of 17α-hydroxypregnenolone to dehydroepiandrosterone and 17α-hydroxyprogesterone to androstenedione, we hypothesize that the unexpected phenotype in cyp17a1-/-;androgen receptor (ar)-/- zebrafish may be mediated through an augmentation of progestin/nuclear progestin receptor (nPgr) signaling. In support of this hypothesis, we show that knockout of cyp17a1 leads to accumulation of 17α,20β-dihydroxy-4-pregnen-3-one (DHP) and P4. Further, administration of progestin, a synthetic DHP mimetic, is sufficient to rescue testicular development and spermatogenesis in ar-/- zebrafish, whereas knockout of npgr abolishes the rescue effect of cyp17a1-/- in the cyp17a1-/-;ar-/- double mutant. Analyses of the transcriptomes among the mutants with defective testicular organization and spermatogenesis (ar-/-, ar-/-;npgr-/- and cyp17a-/-;ar-/-;npgr-/-), those with normal phenotype (Control and cyp17a1-/-), and rescued phenotype (cyp17a1-/-;ar-/-) reveal a common link between a down-regulated expression of insl3 and its related downstream genes in cyp17a-/-;ar-/-;npgr-/- zebrafish. Taken together, our data suggest that genetic or pharmacological augmentation of the progestin/nPgr pathway is sufficient to restore testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling.

Data availability

The knockout fish and genes involved in this study have been cited and clearly listed in the references.

Article and author information

Author details

  1. Gang Zhai

    State key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Tingting Shu

    State key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3020-9329
  3. Guangqing Yu

    State key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Haipei Tang

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Chuang Shi

    State key Laboratory of Freshwater Ecology and Biotechnology, Institute of hydrobiology, Chinese academy of sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Jingyi Jia

    College of Fisheries, Huazhong Agriculture University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Qiyong Lou

    State key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiangyan Dai

    School of Life Science, Southwest University, Chongqing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Xia Jin

    Molecular and Cellular Biology of Aquatic Organisms, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Jiangyan He

    Molecular and Cellular Biology of Aquatic Organisms, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Wuhan Xiao

    Molecular and Cellular Biology of Aquatic Organisms, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2978-0616
  12. Xiaochun Liu

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Zhan Yin

    Molecular and Cellular Biology of Aquatic Organisms, Chinese Academy of Sciences, Wuhan, China
    For correspondence
    zyin@ihb.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7969-3967

Funding

National Key Research and Development Program of China (2018YFD0900205)

  • Zhan Yin

Pilot Program A Project from the Chinese Academy of Sciences (XDA24010206)

  • Zhan Yin

National Natural Science Foundation of China (31972779)

  • Gang Zhai

National Natural Science Foundation of China (31530077)

  • Zhan Yin

National Natural Science Foundation of China (31702027)

  • Xiangyan Dai

Youth Innovation Promotion Association of CAS (2020336)

  • Gang Zhai

State Key Laboratory of Freshwater Ecology and Biotechnology (2016FBZ05)

  • Zhan Yin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experimentation: All fish experiments were conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals and were approved by the Institute of Hydrobiology, Chinese Academy of Sciences (Approval ID: IHB 2013724).

Reviewing Editor

  1. Cunming Duan, University of Michigan, United States

Version history

  1. Received: December 29, 2020
  2. Accepted: February 26, 2022
  3. Accepted Manuscript published: February 28, 2022 (version 1)
  4. Version of Record published: March 10, 2022 (version 2)

Copyright

© 2022, Zhai 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

  • 1,001
    Page views
  • 287
    Downloads
  • 5
    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)

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. Gang Zhai
  2. Tingting Shu
  3. Guangqing Yu
  4. Haipei Tang
  5. Chuang Shi
  6. Jingyi Jia
  7. Qiyong Lou
  8. Xiangyan Dai
  9. Xia Jin
  10. Jiangyan He
  11. Wuhan Xiao
  12. Xiaochun Liu
  13. Zhan Yin
(2022)
Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling
eLife 11:e66118.
https://doi.org/10.7554/eLife.66118

Further reading

    1. Computational and Systems Biology
    2. Developmental Biology
    Mohamad Ibrahim Cheikh, Joel Tchoufag ... Konstantin Doubrovinski
    Research Article

    In order to understand morphogenesis, it is necessary to know the material properties or forces shaping the living tissue. In spite of this need, very few in vivo measurements are currently available. Here, using the early Drosophila embryo as a model, we describe a novel cantilever-based technique which allows for the simultaneous quantification of applied force and tissue displacement in a living embryo. By analyzing data from a series of experiments in which embryonic epithelium is subjected to developmentally relevant perturbations, we conclude that the response to applied force is adiabatic and is dominated by elastic forces and geometric constraints, or system size effects. Crucially, computational modeling of the experimental data indicated that the apical surface of the epithelium must be softer than the basal surface, a result which we confirmed experimentally. Further, we used the combination of experimental data and comprehensive computational model to estimate the elastic modulus of the apical surface and set a lower bound on the elastic modulus of the basal surface. More generally, our investigations revealed important general features that we believe should be more widely addressed when quantitatively modeling tissue mechanics in any system. Specifically, different compartments of the same cell can have very different mechanical properties; when they do, they can contribute differently to different mechanical stimuli and cannot be merely averaged together. Additionally, tissue geometry can play a substantial role in mechanical response, and cannot be neglected.

    1. Developmental Biology
    2. Evolutionary Biology
    Kwi Shan Seah, Vinodkumar Saranathan
    Research Article

    The study of color patterns in the animal integument is a fundamental question in biology, with many lepidopteran species being exemplary models in this endeavor due to their relative simplicity and elegance. While significant advances have been made in unraveling the cellular and molecular basis of lepidopteran pigmentary coloration, the morphogenesis of wing scale nanostructures involved in structural color production is not well understood. Contemporary research on this topic largely focuses on a few nymphalid model taxa (e.g., Bicyclus, Heliconius), despite an overwhelming diversity in the hierarchical nanostructural organization of lepidopteran wing scales. Here, we present a time-resolved, comparative developmental study of hierarchical scale nanostructures in Parides eurimedes and five other papilionid species. Our results uphold the putative conserved role of F-actin bundles in acting as spacers between developing ridges, as previously documented in several nymphalid species. Interestingly, while ridges are developing in P. eurimedes, plasma membrane manifests irregular mesh-like crossribs characteristic of Papilionidae, which delineate the accretion of cuticle into rows of planar disks in between ridges. Once the ridges have grown, disintegrating F-actin bundles appear to reorganize into a network that supports the invagination of plasma membrane underlying the disks, subsequently forming an extruded honeycomb lattice. Our results uncover a previously undocumented role for F-actin in the morphogenesis of complex wing scale nanostructures, likely specific to Papilionidae.