Does Bone Morphogenetic Protein 6 (BMP6) Affect Female Fertility in the Mouse?1

Abstract

Bone morphogenetic protein 6 (BMP6) is a transforming growth factor beta superfamily member produced by mammalian oocytes as well as other cell types. Despite well-characterized effects of recombinant BMP6 on granulosa cells in vitro, the function of BMP6 in vivo has been ill-defined. Therefore, the effects of genetic deletion of the Bmp6 gene on female mouse fertility were assessed. The mean litter size of Bmp6(-/-) females was reduced by 22% (P < 0.05) compared to Bmp6(+/+) controls. Not only did Bmp6(-/-) females naturally ovulate 24% fewer eggs, but competence of in vitro-matured oocytes to complete preimplantation development after fertilization in vitro was decreased by 50%. No apparent effect of Bmp6 deletion on either the morphology or the dynamics of follicular development was apparent. Nevertheless, levels of luteinizing hormone (LH)/human chorionic gonadotropin (hCG)-induced transcripts, which encode proteins required for cumulus expansion (HAS2, PTGS2, PTX3, and TNFAIP6), and of epidermal growth factor-like peptides (AREG, BTC, and EREG) were lower in Bmp6(-/-) mice than in controls after administration of a reduced dose of hCG (1 IU) in vivo. LH receptor (Lhcgr) transcript levels were not significantly lower in Bmp6(-/-) granulosa cells, suggesting that BMP6 is required for processes downstream of LH receptors. To assess whether another oocyte-derived BMP, BMP15, could have BMP6-redundant functions in vivo, the fertility of Bmp15/Bmp6 double mutants was assessed. Fertility was not significantly reduced in double-homozygous mutants compared with that in double-heterozygous controls. Therefore, BMP6 promotes normal fertility in female mice, at least in part, by enabling appropriate responses to LH and normal oocyte quality. Thus, Bmp6 probably is part of the complex genetic network that determines female fertility.