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Structural and biological studies of bone morphogenetic protein-15


The oocyte-secreted growth factor, bone morphogenetic protein-15 (BMP-15) and its close homolog, growth and differentiation factor-9 (GDF-9), are essential factors in the regulation of folliculogenesis and control of ovulation quota. Here, a structural characterization of recombinant human BMP-15 (rhBMP-15) and rhGDF-9 revealed that they are phosphorylated, and phosphorylation is essential for bioactivity. De-phosphorylated rhBMP-15 and rhGDF-9 exhibit potent antagonistic activity toward their phosphorylated counterparts and toward other members of the TGF- [beta] superfamily that share their type II receptors. The de-phosphorylated proteins are capable of receptor binding, but lack the ability to activate their respective Smad signaling pathways. While mutations in sheep BMP-15 and GDF-9 cause infertility due to defects in folliculogenesis in homozygous carriers, defects in mice lacking BMP-15 are confined to the ovulation process and early embryonic development. Here, a study of the expression pattern of mouse BMP-15 mature protein revealed that BMP-15 is barely detected until after the onset of the ovulation process. Following the surges of LH and FSH that occur approximately 12 hours before ovulation, production and secretion of the BMP-15 mature protein increase dramatically and this increase coincides with upregulation of PCSK-9 mRNA, a proprotein convertase (PC) capable of processing the mouse BMP-15 proprotein. The timing of the increased production of the mature protein is directly related to its physiological function during the ovulation process; stimulating cumulus expansion. To examine the function of BMP-15 during folliculogenesis, transgenic mice were generated that over-express mouse BMP -15 exclusively in the oocytes beginning at the primary follicle stage. Immature transgenic mice exhibited accelerated follicle development with a decrease in primary follicles and an increase in secondary follicles. Granulosa cells (GCs) of transgenic mice had increased mitotic activity and decreased follicle-stimulating hormone receptor (FSHR) mRNA expression. Adult mice were fertile and displayed normal litter sizes but had an increased number of atretic antral follicles, likely due to decreased FSH sensitivity. Aging mice exhibited an early onset of acyclicity due to increased diestrus length and an early occurrence of constant diestrus. Thus, these findings answer several fundamental questions regarding the protein structure and physiological functions of BMP- 15

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