Inhibition of oocyte growth factors in vivo modulates ovarian folliculogenesis in neonatal and immature mice.
Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are among the key regulators transmitting the signaling between the oocyte and the surrounding granulosa cells. Previously, it has been shown that a recombinant BMP type II receptor ectodomain-Fc fusion protein (BMPR2ecd-Fc) is able to inhibit the actions of GDF9 and BMP15 in vitro. Here, we have produced bioactive BMPR2ecd-Fc, which was injected i.p. into neonatal mice. Early folliculogenesis was first studied by injecting mice five times with various doses of BMPR2ecd-Fc during the postnatal days 4-12. Folliculogenesis was affected dose dependently, as evidenced by a decreased mitogenesis of granulosa cells of the growing follicles. Furthermore, we also noticed a decrease in the number of secondary and tertiary follicles as well as an increase in the oocyte size. Electron microscopic analysis revealed that the ultrastructure of the granulosa cells of the primary follicles was not affected by the BMPR2ecd-Fc treatment. A second study was conducted to investigate whether a longer treatment with 12 injections during postnatal days 4-28 would inhibit folliculogenesis. Similar effects were observed in the two studies on the early follicular developmental stages. However, in the long-term study, later stages of folliculogenesis were not blocked but rather increased numbers of antral follicles, preovulatory follicles, and corpora lutea were found. We conclude that BMPR2ecd-Fc is a potent modulator of ovarian folliculogenesis in vivo, and thus, is a valuable tool for studying the physiology and downstream effects of oocyte-derived growth factors in vivo.
Myllymaa
Samu
S
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland. samu.myllymaa@helsinki.fi
Pasternack
Arja
A
Mottershead
David G
DG
Poutanen
Matti
M
Pulkki
Minna M
MM
Pelliniemi
Lauri J
LJ
Ritvos
Olli
O
Laitinen
Mika P E
MP
D000818:Animals; D000831:Animals, Newborn; D055430:Bone Morphogenetic Protein 15 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D055429:Growth Differentiation Factor 9 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D009865:Oocytes / Q000187:drug effects* / Q000502:physiology; D009866:Oogenesis / Q000187:drug effects / Q000502:physiology; D006080:Ovarian Follicle / Q000187:drug effects* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012741:Sexual Maturation / Q000502:physiology
D055430:Bone Morphogenetic Protein 15; D055429:Growth Differentiation Factor 9; D007141:Immunoglobulin Fc Fragments; D036341:Intercellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D052006:Bone Morphogenetic Protein Receptors, Type II