Downregulation of Nuclear Progestin Receptor (Pgr) and Subfertility in Double Knockouts of Progestin Receptor Membrane Component 1 (pgrmc1) and Pgrmc2 in Zebrafish

Overview

Journal Gen Comp Endocrinol

Specialty Endocrinology

Date 2019 Sep 20

PMID 31536721

Citations 13

Authors

Xin-Jun Wu

Yong Zhu

Affiliations

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Abstract

The progestin receptor membrane components (Pgrmcs) contain two paralogs, Pgrmc1 and Pgrmc2. Our previous research into single knockout of Pgrmc1 or Pgrmc2 suggests that Pgrmc1 and Pgrmc2 regulate membrane progestin receptor or steroid synthesis and therefore female fertility in zebrafish. Additional roles of Pgrmcs may not be determined in using single Pgrmc knockouts due to compensatory roles between Pgrmc1 and Pgrmc2. To address this question, we crossed single knockout pgrmc1 (pgrmc1) with pgrmc2 (pgrmc2), and generated double knockouts for both pgrmc1 and pgrmc2 (pgrmc1/2) in a vertebrate model, zebrafish. In addition to the delayed oocyte maturation and reduced female fertility, significant reduced ovulation was found in double knockout (pgrmc1/2) in vivo, though not detected in either single knockout of Pgrmc (pgrmc1 or pgrmc2). We also found significant down regulation of nuclear progestin receptor (Pgr) protein expression only in pgrmc1/2, which was most likely the cause of reduced ovulation. Lower protein expression of Pgr also resulted in reduced expression of metalloproteinase in pgrmc1/2. With this study, we have provided new evidence for the physiological functions of Pgrmcs in the regulation of female fertility by regulation of ovulation, likely via regulation of Pgr, which affects regulation of metalloproteinase expression and oocyte ovulation.

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References

Palanisamy G, Cheon Y, Kim J, Kannan A, Li Q, Sato M . A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice. Mol Endocrinol. 2006; 20(11):2784-95. DOI: 10.1210/me.2006-0093. View

Peluso J, Griffin D, Liu X, Horne M . Progesterone receptor membrane component-1 (PGRMC1) and PGRMC-2 interact to suppress entry into the cell cycle in spontaneously immortalized rat granulosa cells. Biol Reprod. 2014; 91(5):104. PMC: 4434922. DOI: 10.1095/biolreprod.114.122986. View

Mittaz L, Russell D, Wilson T, Brasted M, Tkalcevic J, Salamonsen L . Adamts-1 is essential for the development and function of the urogenital system. Biol Reprod. 2003; 70(4):1096-105. DOI: 10.1095/biolreprod.103.023911. View

Ahmed I, Rohe H, Twist K, Craven R . Pgrmc1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity. J Biol Chem. 2010; 285(32):24775-82. PMC: 2915713. DOI: 10.1074/jbc.M110.134585. View

Zhu Y, Hanna R, Schaaf M, Spaink H, Thomas P . Candidates for membrane progestin receptors--past approaches and future challenges. Comp Biochem Physiol C Toxicol Pharmacol. 2008; 148(4):381-9. DOI: 10.1016/j.cbpc.2008.05.019. View

Kabe Y, Nakane T, Koike I, Yamamoto T, Sugiura Y, Harada E . Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. Nat Commun. 2016; 7:11030. PMC: 4802085. DOI: 10.1038/ncomms11030. View

Peluso J, Liu X, Saunders M, Claffey K, Phoenix K . Regulation of ovarian cancer cell viability and sensitivity to cisplatin by progesterone receptor membrane component-1. J Clin Endocrinol Metab. 2008; 93(5):1592-9. DOI: 10.1210/jc.2007-2771. View

Zhu Y, Liu D, Shaner Z, Chen S, Hong W, Stellwag E . Nuclear progestin receptor (pgr) knockouts in zebrafish demonstrate role for pgr in ovulation but not in rapid non-genomic steroid mediated meiosis resumption. Front Endocrinol (Lausanne). 2015; 6:37. PMC: 4365747. DOI: 10.3389/fendo.2015.00037. View

Dubail J, Aramaki-Hattori N, Bader H, Nelson C, Katebi N, Matuska B . A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression. Genesis. 2014; 52(7):702-12. PMC: 4107014. DOI: 10.1002/dvg.22784. View

10.

Rosewell K, Al-Alem L, Zakerkish F, McCord L, Akin J, Chaffin C . Induction of proteinases in the human preovulatory follicle of the menstrual cycle by human chorionic gonadotropin. Fertil Steril. 2014; 103(3):826-33. PMC: 4346449. DOI: 10.1016/j.fertnstert.2014.11.017. View

11.

Aizen J, Pang Y, Harris C, Converse A, Zhu Y, Aguirre M . Roles of progesterone receptor membrane component 1 and membrane progestin receptor alpha in regulation of zebrafish oocyte maturation. Gen Comp Endocrinol. 2018; 263:51-61. PMC: 6480306. DOI: 10.1016/j.ygcen.2018.04.009. View

12.

Press M, Greene G . Localization of progesterone receptor with monoclonal antibodies to the human progestin receptor. Endocrinology. 1988; 122(3):1165-75. DOI: 10.1210/endo-122-3-1165. View

13.

Park O, Mayo K . Transient expression of progesterone receptor messenger RNA in ovarian granulosa cells after the preovulatory luteinizing hormone surge. Mol Endocrinol. 1991; 5(7):967-78. DOI: 10.1210/mend-5-7-967. View

14.

Sriraman V, Eichenlaub-Ritter U, Bartsch J, Rittger A, Mulders S, Richards J . Regulated expression of ADAM8 (a disintegrin and metalloprotease domain 8) in the mouse ovary: evidence for a regulatory role of luteinizing hormone, progesterone receptor, and epidermal growth factor-like growth factors. Biol Reprod. 2008; 78(6):1038-48. DOI: 10.1095/biolreprod.107.066340. View

15.

Ogiwara K, Takano N, Shinohara M, Murakami M, Takahashi T . Gelatinase A and membrane-type matrix metalloproteinases 1 and 2 are responsible for follicle rupture during ovulation in the medaka. Proc Natl Acad Sci U S A. 2005; 102(24):8442-7. PMC: 1150835. DOI: 10.1073/pnas.0502423102. View

16.

Richards J, Ascoli M . Endocrine, Paracrine, and Autocrine Signaling Pathways That Regulate Ovulation. Trends Endocrinol Metab. 2018; 29(5):313-325. DOI: 10.1016/j.tem.2018.02.012. View

17.

Kelly K, Hutchinson G, Nebenius-Oosthuizen D, Smith A, Bartsch J, Horiuchi K . Metalloprotease-disintegrin ADAM8: expression analysis and targeted deletion in mice. Dev Dyn. 2004; 232(1):221-31. DOI: 10.1002/dvdy.20221. View

18.

Carter N, Roach Z, Byrnes M, Zhu Y . Adamts9 is necessary for ovarian development in zebrafish. Gen Comp Endocrinol. 2019; 277:130-140. DOI: 10.1016/j.ygcen.2019.04.003. View

19.

Hanna R, Zhu Y . Controls of meiotic signaling by membrane or nuclear progestin receptor in zebrafish follicle-enclosed oocytes. Mol Cell Endocrinol. 2011; 337(1-2):80-8. DOI: 10.1016/j.mce.2011.02.004. View

20.

Thomas P . Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol. 2008; 29(2):292-312. PMC: 2600886. DOI: 10.1016/j.yfrne.2008.01.001. View