Development of sexual dimorphism of skeletal muscles through the adrenal cortex, caused by androgen-induced global gene suppression
Fumiya Takahashi,
Takashi Baba,
Antonius Christianto,
Shogo Yanai,
Hyeon-Cheol Lee-Okada,
Keisuke Ishiwata,
Kazuhiko Nakabayashi,
Kenichiro Hata,
Tomohiro Ishii,
Tomonobu Hasegawa,
Takehiko Yokomizo,
Man Ho Choi,
Ken-ichirou Morohashi
Affiliations
Fumiya Takahashi
Department of Systems Life Sciences, Graduate School of Systems Life Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Takashi Baba
Department of Systems Life Sciences, Graduate School of Systems Life Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Corresponding author
Antonius Christianto
Department of Systems Life Sciences, Graduate School of Systems Life Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Shogo Yanai
Department of Systems Life Sciences, Graduate School of Systems Life Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Hyeon-Cheol Lee-Okada
Department of Biochemistry, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Keisuke Ishiwata
Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-0074, Japan
Kazuhiko Nakabayashi
Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-0074, Japan
Kenichiro Hata
Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-0074, Japan; Department of Human Molecular Genetics, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
Tomohiro Ishii
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Tomonobu Hasegawa
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Takehiko Yokomizo
Department of Biochemistry, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Man Ho Choi
Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul 02792, Korea
Ken-ichirou Morohashi
Department of Systems Life Sciences, Graduate School of Systems Life Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Internal Medicine, Kurume University School of Medicine, 67 Asahimachi, Kurume 830-0011, Japan; Corresponding author
Summary: 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.
