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Regulation of masculinization: androgen signalling for external genitalia development

Nature Reviews Urology volume 15, pages 358–368 (2018)Cite this article

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Abstract

The biology of masculinization is fundamentally important for understanding the embryonic developmental processes that are involved in the development of the male reproductive tract, external genitalia, and also the tumorigenesis of prostate cancer. The molecular mechanisms of masculinization are of interest to many researchers and clinicians involved in varied fields, including molecular developmental biology, cancer research, endocrinology, and urology. Androgen signalling is mediated by the nuclear androgen receptor, which has fundamental roles in masculinization during development. Various modes of androgen signalling, including 5α-dihydrotestosterone-induced regulation of mesenchymal cell proliferation, have been observed in masculinization. Such regulation is essential for regulating urogenital tissue development, including external genitalia development. Androgen-induced genes, such as MAFB, which belongs to the activator protein 1 (AP-1) superfamily of genes, have essential roles in male urethral formation, and disruption of its signalling can interfere with urethral formation, which often results in hypospadias. Another AP-1 superfamily gene, ATF3, could be responsible for some instances of hypospadias in humans. These androgen-dependent signals and downstream events are crucial for not only developmental processes but also processes of diseases such as hypospadias and prostate cancer.

Key points

  • The molecular mechanisms of masculinization are fundamental topics of many fields of science, including molecular developmental biology, cancer research, endocrinology, and urology.

  • One of the activator protein 1 (AP-1) superfamily genes, MAFB, has been identified as an androgen target gene and has essential roles in male-type urethral formation.

  • Mesenchymal cell proliferation can be regulated by testosterone and 5α-dihydrotestosterone via the androgen receptor.

  • Putatively similar mesenchymal cell characteristics in embryos and prostate-cancer-associated fibroblasts have been described, including the identification of AP-1 superfamily genes.

  • Genes such as ATF3 that are involved in various signalling pathways are affected by oestrogen receptor-mediated cellular processes.

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Fig. 1: The processes of masculinization of the embryonic external genitalia by Mafb.
Fig. 2: ATF3 gene and upstream signals in hypospadias.

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Acknowledgements

The authors thank A. Thomson, L. Baskin, J. Cunha, R. Nishinakamura, S. Takahashi, G. Prins, K.-I. Matsumoto, H. Reutter, and T. DeFalco for their encouragement and discussion points. The authors also thank T. I. Iba and all laboratory colleagues for their assistance. This work was supported by the Japan Society for the Promotion of Science grants 18K06938, 18K06837, 17K18024, 15H04300, 15K15403, 15K10647, 15K19013, and 15J11033.

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  1. These authors contributed equally: Shoko Matsushita, Kentaro Suzuki.

Authors and Affiliations

  1. Department of Developmental Genetics, Wakayama Medical University, Wakayama City, Wakayama, Japan

    Shoko Matsushita, Kentaro Suzuki, Aki Murashima, Daiki Kajioka, Alvin Resultay Acebedo, Shinichi Miyagawa & Gen Yamada

  2. Department of Anatomy, Iwate Medical University, Yahaba, Iwate, Japan

    Aki Murashima

  3. Department of Molecular Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime, Japan

    Ryuma Haraguchi

  4. Faculty of Agriculture, Kyushu University, Higashi-ku, Fukuoka, Japan

    Yukiko Ogino

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S.Ma., K.S., and G.Y. discussed the content, wrote the manuscript, and reviewed and edited the manuscript before submission. A.M., D.K., A.R.A., S.Mi., R.H., and Y.O. discussed the content and wrote the manuscript.

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Matsushita, S., Suzuki, K., Murashima, A. et al. Regulation of masculinization: androgen signalling for external genitalia development. Nat Rev Urol 15, 358–368 (2018). https://doi.org/10.1038/s41585-018-0008-y

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