title: Phospholipase C-related but catalytically inactive proteins regulate ovarian follicle development.
abstract: Phospholipase C-related but catalytically inactive proteins PRIP-1 and -2 are inositol-1,4,5-trisphosphate binding proteins that are encoded by independent genes. Ablation of thePripgenes in mice impairs female fertility, which is manifested by fewer pregnancies, a decreased number of pups, and the decreased and increased secretion of gonadal steroids and gonadotropins, respectively. We investigated the involvement of the PRIPs in fertility, focusing on the ovaries ofPrip-1and-2double-knock-out (DKO) mice. Multiple cystic follicles were observed in DKO ovaries, and a superovulation assay showed a markedly decreased number of ovulated oocytes. Cumulus-oocyte complexes showed normal expansion, and artificial gonadotropin stimulation regulated the ovulation-related genes in a normal fashion, suggesting that the ovulation itself was probably normal. A histological analysis showed atresia in fewer follicles of the DKO ovaries, particularly in the secondary follicle stages. The expression of luteinizing hormone receptor (LHR) was aberrantly higher in developing follicles, and the phosphorylation of extracellular signal-regulated protein kinase, a downstream target of LH-LHR signaling, was higher in DKO granulosa cells. This suggests that the up-regulation of LH-LHR signaling is the cause of impaired follicle development. The serum estradiol level was lower, but estradiol production was unchanged in the DKO ovaries. These results suggest that PRIPs are positively involved in the development of follicles via their regulation of LH-LHR signaling and estradiol secretion. Female DKO mice had higher serum levels of insulin, testosterone, and uncarboxylated osteocalcin, which, together with reduced fertility, are reminiscent of polycystic ovary syndrome in humans.
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: natural@dent.kyushu-u.ac.jp.
authors.forename: Miho
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan; Fukuoka Dental College, Fukuoka 814-0193, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hirata
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000378:metabolism / Q000473:pathology; D006080:Ovarian Follicle / Q000378:metabolism* / Q000473:pathology; D010060:Ovulation / Q000235:genetics; D011085:Polycystic Ovary Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011974:Receptors, LH / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C513987:PRIP-1 phospholipase C-related protein, mouse; C530633:Plcl2 protein, mouse; D011974:Receptors, LH; D004958:Estradiol; D007986:Luteinizing Hormone
keywords: PRIP; estrogen; follicle development; hormone; hormone receptor; luteinizing hormone receptor; ovary; polycystic ovary syndrome; reproduction; reproductive system