Abstract
The androgen receptor (AR) is a nuclear receptor protein family member and inducible transcription factor that modulates androgen target gene expression. Studies using a mouse model confirmed the need for ar in reproductive development, particularly spermatogenesis. Here, we investigated the role of ar in zebrafish using CRISPR/Cas9 gene targeting technology. Targeted disruption of ar in zebrafish increases the number of female offspring and increases offspring weight. In addition, ar-null male zebrafish have female secondary sex characteristics. More importantly, targeted disruption of ar in zebrafish causes male infertility via defective spermatogenesis and female premature ovarian failure during growth. Mechanistic assays suggest that these effects are caused by fewer proliferated cells and more apoptotic cells in ar-null testes. Moreover, genes involved in reproductive development, estradiol induction and hormone synthesis were dys-regulated in testes and ovaries and the reproductive-endocrine axis was disordered. Our data thus suggest that the zebrafish ar is required for spermatogenesis and maintenance of ovarian function, which confirms evolutionarily conserved functions of ar in vertebrates, as well as indicates that ar-null zebrafish are a suitable model for studying pathologic mechanisms related to androgen disorders.
Highlights
The androgen receptor is a member of the nuclear receptor family of proteins that acts as ligandinducible transcription factors, which comprises three main functional domains: the N-terminal transcriptional domain, the DNA binding domain (DBD) and the ligand binding domain (LBD) [1]
Loss of ar caused progressive loss of spermatogenesis and ovarian function, so we suggest that the ar is key to spermatogenesis and maintenance of ovarian function
Targeted disruption of ar produces more female zebrafish and increases weight in male and female zebrafish ar is evolutionarily conserved among zebrafish, mouse, rat and humans, in its DNAbinding domain (DBD) and ligand-binding domain (LBD) (Supplementary Figure 1)
Summary
The androgen receptor (ar) is a member of the nuclear receptor family of proteins that acts as ligandinducible transcription factors, which comprises three main functional domains: the N-terminal transcriptional domain, the DNA binding domain (DBD) and the ligand binding domain (LBD) [1]. Clinical disorders related to ar dysfunction include testicular feminization mutation syndrome (Tfm), prostate cancer and Kennedy’s disease [3,4,5,6]. To elucidate the molecular basis of arrelated disorders, in the last decade, generation and characterization of ar knockout mouse models (ARKO) revealed key roles of the ar in male and female reproduction [10,11,12]. Because the mammalian ar gene is located on the X chromosome, which is critical for male fertility, it is impractical to generate an ARKO mouse line using conventional gene targeting. The ar-mediated androgen actions are important for reproductive development and function, including folliculogenesis, and uterine and mammary gland development [16, 32,33,34,35]
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