Developmental expression and function of Bmp4 in spermatogenesis and in maintaining epididymal integrity

Abstract

Bone morphogenetic proteins (BMPs) play essential roles in many aspects of developmental biology. We have previously shown that Bmp7, Bmp8a, and Bmp8b of the 60A class of Bmp genes have additive effects in spermatogenesis and in maintaining the epididymal integrity of the caput and caudal regions. Here we report that Bmp4 of the Dpp class has a unique expression pattern in the developing testis and epididymis. Bmp4 heterozygous males on a largely C57BL/6 background show compromised fertility due to degeneration of germ cells, reduced sperm counts, and decreased sperm motility. More interestingly, some of these males show extensive degeneration of the epididymal epithelium in the corpus region, rather than in the caput and cauda regions as for Bmp7 and Bmp8 mutants. Thus, these genetic data reveal a region-specific requirement of different classes of BMPs for epididymal epithelium to survive and have significant implications on male reproductive health and perhaps birth control.

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

“…Similar to mice lacking one copy of BMP4, testis development in these mutants appears normal, with effects seen only in the adult testis (Zhao et al, 1996Hu et al, 2004). Using the same reasoning as above, we suggest that, in these cases of reduced BMP expression, compensation by other BMPs is due to their ability to sufficiently activate target genes by means of the ubiquitously expressed SMAD proteins during testis development.…”

“…The survival of BMP8a Ϫ/Ϫ , BMP8b Ϫ/Ϫ , and BMP7 ϩ/Ϫ /8a mutants through embryogenesis and on to adulthood indicates that other BMPs compensate sufficiently for reduced expression or absence of these ligands (Zhao et al, 1996Hu et al, 2004). Similar to mice lacking one copy of BMP4, testis development in these mutants appears normal, with effects seen only in the adult testis (Zhao et al, 1996Hu et al, 2004).…”

“…In BMP4 ϩ/Ϫ mice, BMP4 is expressed at sufficient levels to permit survival during embryogenesis and on to adulthood. Testis development appears normal, with effects only seen in the adult testis (Hu et al, 2004). Therefore, in the developing testis, in an environment of reduced availability of BMP4, other BMPs may sufficiently compensate due to the signal transducing SMAD1, SMAD5, and SMAD8 in target cells being ubiquitously expressed.…”

“…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

“…BMP/SMAD signaling has previously been implicated in germline development in Drosophila, mice, and humans (12,14,29,34,35). BMP4 stimulates the proliferation and differentiation of spermatogonial stem cells in vitro (12).…”