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

Abstract

Mutation in either of the genes encoding bone morphogenetic protein (BMP) 8A or 8B ( or ) causes postnatal depletion of spermatogonia in mice. We found that, but not , 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.

The protective effects of MSC-EXO against pulmonary arterial hypertension through inhibition of Wnt/BMP signaling pathway

“…BMPs signaling could stimulate activation of SMAD transcription factors through heteromeric receptor complexes [20]. Inhibition of BMP/SMAD signaling directly leads to a reduction in SMAD1/5/8 pathway and to a concomitant increase in SMAD2/3 pathway, and change the gene transcription regulation of the pulmonary fibrosis occurrence [21].…”

Sublytic C5b‐9 induces proliferation of glomerular mesangial cells via ERK5/MZF1/RGC‐32 axis activated by FBXO28‐TRAF6 complex

“…It is well accepted that cell proliferation is related to the overexpression of some pro‐proliferative genes . Response gene to complement 32 (RGC‐32) was first identified in the oligodendrocytes stimulated with complement .…”

“…It is well accepted that cell proliferation is related to the overexpression of some pro-proliferative genes. 13 Response gene to complement 32 (RGC-32) was first identified in the oligodendrocytes stimulated with complement. 14 Reportedly, RGC-32 overexpression is correlated with the proliferation of endothelial cells, smooth muscle cells and colon cancer cells in response to a variety of stimuli including sublytic C5b-9.…”

Transcription factors—Intricate players of the bone morphogenetic protein signaling pathway

“…Receptor‐regulated SMADs (R‐SMADs) of the BMP family (SMAD1/5/9) bind to the activated receptor complex and are phosphorylated by the type I receptors . Interestingly, there has been recent evidence that BMPs can also signal through the TGFβ pathway R‐SMADs (SMAD2 and SMAD3) in immortalized human granulosa cells, sprematogonia as well as various cancer and epithelial cells . Similarly, TGFβ is also able to activate the SMAD1,5 in a cell type dependent manner .…”

“…15 Interestingly, there has been recent evidence that BMPs can also signal through the TGFb pathway R-SMADs (SMAD2 and SMAD3) in immortalized human granulosa cells, sprematogonia as well as various cancer and epithelial cells. [16][17][18] Genes Chromosomes Cancer. 2018;57:3-11.…”