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

Zhai, Gang; Shu, Tingting; Yu, Guangqing; Tang, Haipei; Shi, Chuang; Jia, Jingyi; Lou, Qiyong; Dai, Xiangyan; Jin, Xia; He, Jiangyan; Xiao, Wuhan; Liu, Xiaochun; Yin, Zhan

doi:10.7554/eLife.66118

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

Journal Article · Mon Feb 28 00:00:00 EST 2022 · eLife

DOI:https://doi.org/10.7554/eLife.66118· OSTI ID:1854261

Zhai, Gang;

; Yu, Guangqing; Tang, Haipei; Shi, Chuang; Jia, Jingyi; Lou, Qiyong; Dai, Xiangyan; Jin, Xia; He, Jiangyan;

; Liu, Xiaochun;

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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Sponsoring Organization:: USDOE Office of Electricity (OE), Advanced Grid Research & Development. Power Systems Engineering Research

OSTI ID:: 1854261

Alternate ID(s):: OSTI ID: 1854266

Journal Information:: eLife, Journal Name: eLife Vol. 11; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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