Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling
- Chinese Academy of Sciences, China
- Sun Yat-sen University, China
- Institute of hydrobiology, Chinese academy of sciences, China
- Huazhong Agriculture University, China
- 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.
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Author details
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
- Cunming Duan, University of Michigan, United States
Version history
- Received: December 29, 2020
- Accepted: February 26, 2022
- Accepted Manuscript published: February 28, 2022 (version 1)
- 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.
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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
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