Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling
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
Affiliations
Gang Zhai
State 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
State 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, China
Guangqing Yu
State 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
Haipei Tang
5State 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, China
Chuang Shi
State 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
Jingyi Jia
College of Fisheries, Huazhong Agriculture University, Wuhan, China
Qiyong Lou
State Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China
Xiangyan Dai
Key Laboratory of Freshwater Fish Reproduction and Development and Key Laboratory of Aquatic Science of Chongqing, School of Life Science, Southwest University, Chongqing, China
Xia Jin
State Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China
Jiangyan He
State Key Laboratory of Freshwater Ecology and Biotechnology, Chinese Academy of Sciences, Wuhan, China
State 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, China
Xiaochun Liu
5State 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, China
State 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, China
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.
