Yuki Ikeda1, Akiko Hasegawa2, Hiroshi Tsubamoto1, Yu Wakimoto1, Kanako Kumamoto3, Hiroaki Shibahara1. 1. Department of Obstetrics and Gynecology, Hyogo College of Medicine, Mukogawa-cho, 1-1, Nishinomiya, Hyogo 663-8501, Japan. 2. Department of Obstetrics and Gynecology, Hyogo College of Medicine, Mukogawa-cho, 1-1, Nishinomiya, Hyogo 663-8501, Japan; Institute of Animal Experimental Sciences, Hyogo College of Medicine, Mukogawa-cho, 1-1, Nishinomiya, Hyogo 663-8501, Japan. Electronic address: zonapel@hyo-med.ac.jp. 3. Department of Genetic Disease Research, Osaka City University, Graduate School of Medicine, Asahi-machi, 1-4-3, Abeno, Osaka 545-8586, Japan.
Abstract
OBJECTIVE: To investigate the localization and function of gremlin-2 during human ovarian folliculogenesis. STUDY DESIGN: Ovarian tissue from a gynecologic cancer patient was cultured in the presence or absence of gremlin-2 and then analyzed histologically. Growing follicles were counted by the microscopic observations of ovarian histological sections. Immunocytochemical staining was carried out to detect the expression of bone morphogenetic protein (BMP) 4 and phosphorylated Smad 1/5/8 (p-Smad 1/5/8). RESULTS: Gremlin-2 was detected in human primordial, primary, and early growing follicles before culture. By day 4 of culture, the follicle growth rate in the presence of gremlin-2 (13.7%; 24/175) was significantly lower than that of the control (54.8%; 92/175; p<0.01). BMP4 expression was similar in the presence and absence of gremlin-2, whereas the p-Smad 1/5/8 signal was noticeably stronger in the absence of gremlin-2 in primordial and early-stage growing follicles. CONCLUSIONS: Gremlin-2 maintains the follicle store as primordial follicles by suppressing Smad 1/5/8 signaling in the human ovary. The data presented here provide potential insight into reproductive medicine for cases of intractable infertility, such as premature ovarian insufficiency and cancer survivors.
OBJECTIVE: To investigate the localization and function of gremlin-2 during human ovarian folliculogenesis. STUDY DESIGN: Ovarian tissue from a gynecologic cancerpatient was cultured in the presence or absence of gremlin-2 and then analyzed histologically. Growing follicles were counted by the microscopic observations of ovarian histological sections. Immunocytochemical staining was carried out to detect the expression of bone morphogenetic protein (BMP) 4 and phosphorylated Smad 1/5/8 (p-Smad 1/5/8). RESULTS:Gremlin-2 was detected in human primordial, primary, and early growing follicles before culture. By day 4 of culture, the follicle growth rate in the presence of gremlin-2 (13.7%; 24/175) was significantly lower than that of the control (54.8%; 92/175; p<0.01). BMP4 expression was similar in the presence and absence of gremlin-2, whereas the p-Smad 1/5/8 signal was noticeably stronger in the absence of gremlin-2 in primordial and early-stage growing follicles. CONCLUSIONS:Gremlin-2 maintains the follicle store as primordial follicles by suppressing Smad 1/5/8 signaling in the human ovary. The data presented here provide potential insight into reproductive medicine for cases of intractable infertility, such as premature ovarian insufficiency and cancer survivors.