Androgen-regulated MafB drives cell migration via MMP11-dependent extracellular matrix remodeling in mice
Mellissa C. Alcantara,
Kentaro Suzuki,
Alvin R. Acebedo,
Daiki Kajioka,
Satoshi Hirohata,
Tsuneyasu Kaisho,
Yu Hatano,
Kazuo Yamagata,
Satoru Takahashi,
Gen Yamada
Affiliations
Mellissa C. Alcantara
Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Kentaro Suzuki
Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan; Corresponding author
Alvin R. Acebedo
Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Daiki Kajioka
Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan
Satoshi Hirohata
Department of Medical Technology, Graduate School of Health Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 Japan
Tsuneyasu Kaisho
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera, Wakayama 641-8509, Japan
Yu Hatano
Faculty of Biology-Oriented Science and Technology, Kindai University, Kinokawa-shi, Wakayama 649-6493, Japan
Kazuo Yamagata
Faculty of Biology-Oriented Science and Technology, Kindai University, Kinokawa-shi, Wakayama 649-6493, Japan
Satoru Takahashi
Department of Anatomy and Embryology, Laboratory Animal Resource Center in Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305, Japan
Gen Yamada
Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan; Corresponding author
Summary: While androgen is considered a pivotal regulator of sexually dimorphic development, it remains unclear how it orchestrates the differentiation of reproductive organs. Using external genitalia development as a model, we showed that androgen, through the transcription factor MafB, induced cell migration by remodeling the local extracellular matrix (ECM), leading to increased cell contractility and focal adhesion assembly. Furthermore, we identified the matrix metalloproteinase Mmp11 as a MafB target gene under androgen signaling. MMP11 remodels the local ECM environment by degrading Collagen VI (ColVI). The reduction of ColVI led to the fibrillar deposition of fibronectin in the MafB-expressing bilateral mesenchyme both in vivo and ex vivo. The ECM remodeling and development of migratory cell characteristics were lost in the MafB loss-of-function mice. These results demonstrate the requirement of mesenchymal-derived androgen signaling on ECM-dependent cell migration, providing insights into the regulatory cellular mechanisms underlying androgen-driven sexual differentiation.
