Downregulation of nuclear progestin receptor (Pgr) and subfertility in double knockouts of progestin receptor membrane component 1 (pgrmc1) and pgrmc2 in zebrafish

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.

The Interface of Nuclear and Membrane Steroid Signaling

“…Global knockout of pgrmc1 in zebrafish resulted in reduced fertility, presumably due to impaired oocyte maturation ( 83 ). Similar results were obtained in a follow-up study, where double knockout of pgrmc1/2 resulted in reduced fertility, presumably due to reduced oocyte ovulation ( 84 ). A role for PGRMC1 in granulosa cell mitosis and survival was also demonstrated via conditional knockout in murine granulosa cells ( 85 ).…”

Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses

“…Progesterone receptor membrane component 1 (Pgrmc1) (Nomenclature: mouse gene: Pgrmc1 , human gene: PGRMC1 , zebrafish gene pgrmc1 , protein: PGRMC1) belongs to the membrane-associated progesterone receptor (MAPR) gene family and contains the N-terminal transmembrane domain and C-terminal cytochrome b5-like heme-binding domain [ 20 ]. Since it mediates progesterone’s actions, abnormal phenotypes have been reported in Pgrmc1 female mutants: Pgr cre-mediated Pgrmc1 conditional knockout (cKO) in female reproductive tracts exhibited an impaired uterine environment in mice with its ovarian function left normal [ 21 ], while the subfertility in pgrmc1 global KO zebrafish resulted from an impaired ovarian function [ 22 , 23 ], and their uterine- and ovarian-specific abnormalities were seen also in Pgrmc1 /2 cKO mice [ 24 ] and pgrmc1/2 global KO zebrafish [ 22 , 23 ], respectively. Moreover, endonuclease mediated global Pgrmc1 KO mice showed a defective development of mammary gland [ 25 ].…”

Probiotic Administration Mitigates Bisphenol A Reproductive Toxicity in Zebrafish

“…Zebrafish pgrmc1 −/− show a reduction of fecundity and fertility [51] and similarly, in female mice, conditional ablation of pgrmc1 results in reduced fertility, while elimination of pgrmc2 causes premature reproductive senescence [52]. In class III oocytes isolated from fish exposed to BPA or P, an increase in the expression of form 1 and a down-regulation of form 2 was observed and therefore since they are both involved in the maturation process [53], this could result in the lack of increase of maturing oocytes, despite the higher number of vitellogenic ones. In BPA+P group, mRNA transcripts suggest the ability of P to antagonize BPA as clearly demonstrated by levels similar to C ones.…”