Zebrafish cyp17a1 knockout reveals that androgen-mediated signaling is important for male brain sex differentiation

Shu, T., Zhai, G., Pradhan, A., Olsson, P.E., Yin, Z.
General and comparative endocrinology   295: 113490 (Journal)
Registered Authors
Pradhan, Ajay, Yin, Zhan, Zhai, Gang
Brain dimorphism, Neurons, RNA sequencing, Sexual dimorphism, Steroids
MeSH Terms
  • Androgens/metabolism*
  • Animals
  • Behavior, Animal
  • Brain/physiology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Knockout Techniques*
  • Gene Ontology
  • Male
  • Sex Differentiation*/genetics
  • Signal Transduction*
  • Steroid 17-alpha-Hydroxylase
  • Testosterone/analogs & derivatives
  • Testosterone/metabolism
  • Zebrafish/physiology*
  • Zebrafish Proteins/deficiency*
32283058 Full text @ Gen. Comp. Endocrinol.
Brain sex differentiation is a complex process, wherein genes and steroid hormones act to induce specific gender brain differentiation. Testosterone (T) derived from the gonads has been linked to neural circuit modeling in a sex-specific manner. Previously, we have shown that cyp17a1 knockout (KO) zebrafish have low plasma androgen levels, and display compromised male-typical mating behaviors. In this study, we demonstrated that treatment of cyp17a1 KO males with T or 11-ketotestosterone (11-KT) is sufficient to rescue mating impairment by restoring the male-typical secondary sex characters (SSCs) and mating behaviors, confirming an essential role of androgen in maintaining SSCs and mating behaviors. Brain steroid hormone analysis revealed that cyp17a1 KO fish have reduced levels of T and 11-KT. We performed RNA sequencing on brain samples of control and cyp17a1 KO male zebrafish to get insights regarding the impact of cyp17a1 KO on gene expression pattern, and to correlate it with the observed disruption of male-typical mating behaviors. Transcriptome analysis of cyp17a1 KO males showed a differential gene expression when compared to control males. In total, 358 genes were differentially regulated between control males and KO males. Important genes including brain aromatase (cyp19a1b), progesterone receptor (pgr), deiodinase (dio2), and insulin-like growth factor 1 (igf1) that are involved in brain functions, as well as androgen response genes including igf1, frem1a, elovl1a, pax3a, mmp13b, hsc70, ogg1 were regulated. RT-qPCR analysis following rescue of cyp17a1 KO with T and 11-KT further suggested that androgen-mediated signaling is disrupted in the cyp17a1 KO fish. Our results indicated that cyp17a1 KO fish have an incomplete masculinization and altered brain gene expression, which could be due to decreased androgen levels.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes