BMP8A sustains spermatogenesis by activating both SMAD1/5/8 and SMAD2/3 in spermatogonia
Journal
Science Signaling
Journal Volume
10
Journal Issue
477
Date Issued
2017
Author(s)
Abstract
Mutation in either of the genes encoding bone morphogenetic protein (BMP) 8A or 8B (Bmp8a or Bmp8b) causes postnatal depletion of spermatogonia in mice. We found that Bmp8a, but not Bmp8b, was expressed predominantly in the neonatal mouse spermatogonia. Although most BMPs induce activation of SMADs 1, 5, and 8 (SMAD1/5/8), but not SMADs 2 and 3 (SMAD2/3), we found that BMP8A induced signaling through both sets of transcription factors. In undifferentiated mouse spermatogonia, BMP8A activated SMAD1/5/8 through receptor complexes formed by ALK3 and either ACVR2A or BMPR2 and activated SMAD2/3 through receptor complexes formed by ALK5 and ACVR2A, ACVR2B, or TGFBR2. Signaling through SMAD2/3 promoted the proliferation of germ cells, whereas that through SMAD1/5/8 directed the subsequent differentiation of spermatogonia. BMP8A promoted spermatogenesis in cultured mouse testis explants, and the resulting spermatids were functionally competent for fertilization. These results suggest that the dual role of BMP8A in promoting proliferation and differentiation of spermatogonia may be exploited clinically to treat male infertility. ? 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
SDGs
Other Subjects
activin A receptor type 2A; activin A receptor type 2B; bone morphogenetic protein; bone morphogenetic protein 8a; bone morphogenetic protein receptor 1A; receptor; Smad protein; Smad1 protein; Smad2 protein; Smad3 protein; Smad5 protein; Smad8 protein; transforming growth factor beta receptor 2; unclassified drug; BMP8A protein, human; Bmp8a protein, mouse; bone morphogenetic protein; receptor regulated Smad protein; animal cell; animal tissue; Article; cell differentiation; cell proliferation; controlled study; ex vivo study; gene expression; germ cell; HEK293T cell line; human; human cell; in vitro study; male; mouse; nonhuman; priority journal; signal transduction; spermatid; spermatogenesis; spermatogonium; animal; cell culture; cell differentiation; cytology; Institute for Cancer Research mouse; metabolism; physiology; spermatogenesis; spermatogonium; Animals; Bone Morphogenetic Proteins; Cell Differentiation; Cells, Cultured; Humans; Male; Mice; Mice, Inbred ICR; Signal Transduction; Smad Proteins, Receptor-Regulated; Spermatogenesis; Spermatogonia
Type
journal article