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 the Prip genes 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 of Prip-1 and -2 double-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.
Highlights
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
After injecting the mice with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin, the ovulated oocytes were collected from the oviducts and counted
The expression level, and the temporal regulation of luteinizing hormone receptor (LHR) is affected in DKO mice
Summary
Phospholipase C-related but catalytically inactive proteins PRIP-1 and -2 were first identified as D-myo-inositol 1,4,5-trisphosphate (Ins[1,4,5]P3) binding proteins [4, 5]. The isolated anterior lobes of the pituitary glands from DKO females secreted more gonadotropins in response to a gonadotropin-releasing-hormone-mimicking peptide in comparison to WT females, sugtoxylin and eosin; hCG, human chorionic gonadotropin; LH, luteinizing hormone; LHR, luteinizing hormone receptor; MAPK, mitogen-activated protein kinase; OC, osteocalcin; PRIP (Prip), phospholipase C-related but catalytically inactive protein (gene); PGE2, prostaglandin E2; PCOS, polycystic ovary syndrome; PMSG, pregnant mare serum gonadotropin; qPCR, quantitative real-time polymerase chain reaction; PH, pleckstrin homology; Ins[1,4,5]P3, D-myo-inositol 1,4,5-trisphosphate. Gesting that the higher secretion of gonadotropin that was observed does not occur through a feedback loop in the HPG axis [25] These results and our previous studies suggest that PRIPs are negatively involved in exocytosis in the pituitary gland, which leads to the secretion of peptide hormones [12, 13, 25]. The phenotype partly resembles PCOS, which is one of the most common endocrinopathies affecting women of reproductive age worldwide [3, 26, 27]
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