Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling
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....
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eLife Sciences Publications Ltd
2022-02-01
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Online Access: | https://elifesciences.org/articles/66118 |
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author | Gang Zhai Tingting Shu Guangqing Yu Haipei Tang Chuang Shi Jingyi Jia Qiyong Lou Xiangyan Dai Xia Jin Jiangyan He Wuhan Xiao Xiaochun Liu Zhan Yin |
author_facet | Gang Zhai Tingting Shu Guangqing Yu Haipei Tang Chuang Shi Jingyi Jia Qiyong Lou Xiangyan Dai Xia Jin Jiangyan He Wuhan Xiao Xiaochun Liu Zhan Yin |
author_sort | Gang Zhai |
collection | DOAJ |
description | 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 converts 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 downregulated 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. |
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language | English |
last_indexed | 2024-12-10T04:40:30Z |
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spelling | doaj.art-11cac713e06841ffb265aadbd1c0e4e52022-12-22T02:01:53ZengeLife Sciences Publications LtdeLife2050-084X2022-02-011110.7554/eLife.66118Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signalingGang Zhai0Tingting Shu1https://orcid.org/0000-0002-3020-9329Guangqing Yu2Haipei Tang3Chuang Shi4Jingyi Jia5Qiyong Lou6Xiangyan Dai7Xia Jin8Jiangyan He9Wuhan Xiao10https://orcid.org/0000-0002-2978-0616Xiaochun Liu11Zhan Yin12https://orcid.org/0000-0002-7969-3967State Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, ChinaState Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China; Chinese Sturgeon Research Institute, China Three Gorges Corporation, Hubei, ChinaState Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China5State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaState Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, ChinaCollege of Fisheries, Huazhong Agriculture University, Wuhan, ChinaState Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, ChinaKey Laboratory of Freshwater Fish Reproduction and Development and Key Laboratory of Aquatic Science of Chongqing, School of Life Science, Southwest University, Chongqing, ChinaState Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, ChinaState Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, ChinaState Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China; The Innovative Academy of Seed Design, Chinese Academy of Sciences, Wuhan, China5State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaState Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China; The Innovative Academy of Seed Design, Chinese Academy of Sciences, Wuhan, ChinaDisruption 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 converts 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 downregulated 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.https://elifesciences.org/articles/66118testis organizationspermatogenesisandrogen signaling |
spellingShingle | Gang Zhai Tingting Shu Guangqing Yu Haipei Tang Chuang Shi Jingyi Jia Qiyong Lou Xiangyan Dai Xia Jin Jiangyan He Wuhan Xiao Xiaochun Liu Zhan Yin Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling eLife testis organization spermatogenesis androgen signaling |
title | Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling |
title_full | Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling |
title_fullStr | Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling |
title_full_unstemmed | Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling |
title_short | Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling |
title_sort | augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling |
topic | testis organization spermatogenesis androgen signaling |
url | https://elifesciences.org/articles/66118 |
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