Research ArticleDevelopmental Biology

BMP8A sustains spermatogenesis by activating both SMAD1/5/8 and SMAD2/3 in spermatogonia

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Sci. Signal.  02 May 2017:
Vol. 10, Issue 477, eaal1910
DOI: 10.1126/scisignal.aal1910

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BMP8A activates SMAD1/5/8 and SMAD2/3 simultaneously

Like other members of the transforming growth factor–β (TGF-β) superfamily, bone morphogenetic proteins (BMPs) signal through heteromeric receptor complexes to stimulate activation of SMAD transcription factors. Whereas TGF-βs typically activate SMAD2/3, BMPs typically stimulate activation of SMAD1/5/8. Wu et al. found that BMP8A stimulated activation of both SMAD2/3 and SMAD1/5/8 in mouse spermatogonia. BMP8A acted through different sets of receptor complexes to stimulate each set of SMADs. Signaling through SMAD2/3 was important for proliferation of spermatogonia, and signaling through SMAD1/5/8 was important for the differentiation of spermatogonia into spermatids. These findings identify an unusual signaling mechanism for BMP8A and suggest that BMP8A might be useful for treating male infertility because BMP8A treatment enhanced the in vitro production of functional sperm in mouse testis explants.

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.

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