Regulatory role of BMP2 and BMP7 in spermatogonia and Sertoli cell proliferation in the immature mouse

Abstract

Aim: The aim of this study was to determine the action of bone morphogenetic proteins (BMPs) on testicular cell proliferation during early postnatal life, a definite developmental time at which crucial changes in germ cell and Sertoli cell maturation occur. Methods: We investigated the effect of BMP2 and BMP7, two factors which belong to the relatively distant decapentaplegic (DPP) and 60A classes of the large BMP family, upon spermatogonial and Sertoli cell proliferation, and we examined the expression of activin/BMP type II and type I receptors. We used in vitro cultured testis fragments from 7-day-old mice, highly purified populations of somatic and germ cells and total testes from mice of different ages. Cell proliferation was assessed by BrdU labelling and [ 3 H]-thimidine incorporation. Ribonuclease protection assays and Northern blotting were performed to analyse receptor expression. Results and conclusions:We have demonstrated a stimulatory action of BMP2 and BMP7 in spermatogonia and Sertoli cell proliferation respectively. ActRIIB is the type II receptor expressed most in spermatogonia, whereas Sertoli cells specifically expressed BMPRIIB, in addition to ActRIIB. By contrast, the presence of ActRIIA was undetectable in either germ or somatic cells. The type I receptors ActRIA, ActRIB and BMPRIA were all found in both cell types, indicating that the observed effect of BMP2 and BMP7 on testicular cell proliferation may be mediated by a number of combinatorial interactions in the receptor complexes. These findings suggest that BMPs are involved in physiological paracrine signalling during the first wave of spermatogenesis.European Journal of Endocrinology 151 511-520

SMAD expression in the testis: An insight into BMP regulation of spermatogenesis

“…11a). Following stimulation of Sertoli/ germ cell cocultures with BMP2 and BMP4 at concentrations used in previous studies (Pellegrini et al, 2003;Puglisi et al, 2004), Western blot analysis confirmed that both BMP2 and BMP4 increased SMAD1/5/8 phosphorylation relative to untreated control samples, with an increase in intensity of a band that colocalizes with SMAD5 (Fig. 11b).…”

“…upon, cells of prepubertal testis (Pellegrini et al, 2003;Puglisi et al, 2004), with BMP2 and BMP4 implicated in spermatogonial proliferation and differentiation (Pellegrini et al, 2003;Puglisi et al, 2004) and BMP7 in Sertoli cell proliferation (Puglisi et al, 2004).…”

“…The impact of numerous BMPs on the survival and proliferation of murine germ cells during embryonic development and the regulation of postnatal germ cell and somatic cell populations has been identified from in vitro and in vivo studies (Jorgez et al, 2005;Loveland and Hime, 2005;Itman et al, 2006). BMP4, BMP8a, and BMP8b regulate primordial germ cell (PGC) specification in the fetus (Ying et al, 2000;Ying and Zhao, 2001), whereas in in vitro assays, BMP2 and BMP4 enhance juvenile spermatogonial proliferation (Pellegrini et al, 2003;Puglisi et al, 2004) and BMP4 can influence spermatogonial differentiation (Pellegrini et al, 2003;Baleato et al, 2005). BMP8b has also been implicated in the regulation of prepubertal germ cell proliferation at the onset of spermatogenesis, while BMP4, BMP8a and BMP8b are required for complete maintenance of adult spermatogenesis in vivo (Zhao et al, 1996;1998;Hu et al, 2004).…”

Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish

“…Multiple ligands in the TGF-β superfamily are thought to play a role in this process, including TGF-β, BMPs, anti-Mullerian hormone (AMH), and GDNF. BMP signaling is required for the specification of primordial germ cells during embryogenesis (30)(31)(32), and contributes, along with GDNF signaling, to the selfrenewal of spermatogonial stem cells (13,14) and the maintenance of spermatogenesis (16). Here we present evidence that alk6/BMPR1B is cell-autonomously required for germ-cell differentiation.…”

“…In vitro, exogenous BMP4 appears to drive the differentiation of spermatogonial stem cells from enriched germ-cell cultures (11,12). BMP2 and glial-derived neurotrophic factor (GDNF), also a TGF-β family ligand, have likewise been implicated in the regulation of spermatogonial stem cell self-renewal (13,14). In mouse models, inactivation of BMP8b led to reduced or delayed germ-cell proliferation and differentiation during the first wave of spermatogenesis at puberty, and increased apoptosis of pachytene spermatocytes, leading to reduced fertility in the adult (15).…”