Bone morphogenetic protein-15 - Identification of target cells and biological functions

In developing ovarian follicles, the regulation of cell proliferation and d ifferentiation is tightly coordinated, Precisely how this coordination is a chieved is unknown, but recent observations have suggested that molecules e mitted by the oocyte are involved in the process. The newly discovered oocy te-specific growth factor, bone morphogenetic protein-15 (BMP-15), is one s uch molecule,At present, nothing is known about the target cells and biolog ical functions of BMP-15. To fill this gap in our knowledge, recombinant BM P-15 and its antibody were produced and used to determine BMP-15 expression and bioactivity, BMP-15 mRNA and protein were shown to be co-expressed in oocytes throughout folliculogenesis, supporting the idea that BMP-15 is a p hysiological regulator of follicle cell proliferation and/or differentiatio n. To test this, we used primary cultures of rat granulosa cells (GCs), We found that BMP-15 is a potent stimulator of GC proliferation and importantl y, the mitogenic effect was follicle-stimulating hormone (FSH)-independent. By contrast, BMP-15 alone had no effect on steroidogenesis. However, it pr oduced a marked decrease in FSH-induced progesterone production, but had no effect on FSH stimulated estradiol production. This result indicates that BMP-15 is a selective modulator of FSH action. In summary, this study ident ifies GCs as the first target cells for BMP-15. Moreover, it identifies the stimulation of GC proliferation and the differential regulation of two cru cial steroid hormones as the first biological functions of BMP-15, Signific antly, BMP-15 is the first growth factor that can coordinate GC proliferati on and differentiation in a way that reflects normal physiology.