Effects of gremlin-2 on the transition of primordial follicles during early folliculogenesis in the human ovary.
OBJECTIVE
To investigate the localization and function of gremlin-2 during human ovarian folliculogenesis.


METHODS
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.
Department of Obstetrics and Gynecology, Hyogo College of Medicine, Mukogawa-cho, 1-1, Nishinomiya, Hyogo 663-8501, Japan.
Yuki
Y
Ikeda
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.
Akiko
A
Hasegawa
Department of Obstetrics and Gynecology, Hyogo College of Medicine, Mukogawa-cho, 1-1, Nishinomiya, Hyogo 663-8501, Japan.
Hiroshi
H
Tsubamoto
Department of Obstetrics and Gynecology, Hyogo College of Medicine, Mukogawa-cho, 1-1, Nishinomiya, Hyogo 663-8501, Japan.
Yu
Y
Wakimoto
Department of Genetic Disease Research, Osaka City University, Graduate School of Medicine, Asahi-machi, 1-4-3, Abeno, Osaka 545-8586, Japan.
Kanako
K
Kumamoto
Department of Obstetrics and Gynecology, Hyogo College of Medicine, Mukogawa-cho, 1-1, Nishinomiya, Hyogo 663-8501, Japan.
Hiroaki
H
Shibahara
D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D016207:Cytokines; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D006080:Ovarian Follicle / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010053:Ovary / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D016207:Cytokines; C495107:GREM2 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051785:Smad Proteins
BMP; Oncofertility; Ovarian culture; Ovarian preservation; Smad 1/5/8