Development of sexual dimorphism of skeletal muscles through the adrenal cortex, caused by androgen-induced global gene suppression.

The zona fasciculata (zF) in the adrenal cortex contributes to multiple physiological actions through glucocorticoid synthesis. The size, proliferation, and glucocorticoid synthesis characteristics are all female biased, and sexual dimorphism is established by androgen. In this study, transcriptomes were obtained to unveil the sex differentiation mechanism. Interestingly, both the amount of mRNA and the expressions of nearly all genes were higher in females. The expression of Nr5a1 , which is essential for steroidogenic cell differentiation, was also female biased. Whole-genome studies demonstrated that NR5A1 regulates nearly all gene expression directly or indirectly. This suggests that androgen-induced global gene suppression is potentially mediated by NR5A1. Using Nr5a1 heterozygous mice, whose adrenal cortex is smaller than the wild type, we demonstrated that the size of skeletal muscles is possibly regulated by glucocorticoid synthesized by zF. Taken together, considering the ubiquitous presence of glucocorticoid receptors, our findings provide a pathway for sex differentiation through glucocorticoid synthesis. [Display omitted] • Adrenal zona fasciculata cells show globally female-biased transcription • Nr5a1 governs gene expression globally in adrenal zona fasciculata cells • Androgen suppresses cellular transcription globally via suppressing Nr5a1 • Sexually dimorphic corticosterone levels trigger sex difference in skeletal muscles Takahashi et al. demonstrate globally female-biased transcription impacting glucocorticoid synthesis in adrenocortical zona fasciculata cells. NR5A1 (Ad4BP/SF-1) possibly mediates androgen-induced suppression of global transcription. This study suggests a pathway for sex differentiation via glucocorticoid synthesis, affecting various tissues due to the ubiquitous expression of glucocorticoid receptor. [ABSTRACT FROM AUTHOR]