Pgrmc1 Knockout Impairs Oocyte Maturation in Zebrafish

Abstract

Recent investigations suggest progestin receptor membrane component 1 (PGRMC1) associates with and transports a wide range of molecules such as heme, cytochromes P450, steroids with 21 carbons, membrane progestin receptor alpha (mPRα/Paqr7), epidermal growth factor receptor (EGFR), and insulin receptor. It is difficult to discriminate the true functions of PGRMC1 from the functions of its associated molecules using biochemical and pharmacological approaches. To determine the physiological function(s) of PGRMC1, we generated global knockouts for pgrmc1 (pgrmc1−/−) in zebrafish. We found a reduction in both spawning frequency and the number of embryos produced by female mutants. We also observed reduced sensitivity of fully-grown immature oocytes to a progestin hormone and a reduced number of oocytes undergone meiotic maturation both in vivo and in vitro in pgrmc1−/−. This reduced sensitivity to progestin corresponds well with significant reduced expression of mPRα, the receptor mainly responsible for mediating oocyte maturation and meiosis resumption in fish. The results provide in vivo and in vitro evidence for the physiological functions of Pgrmc1 in oocyte maturation and fertility, as well as a plausible molecular mechanism via regulation of mPRα, which in turn directly regulates oocyte maturation and affects fertility in zebrafish.

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

“…Sabbir recently demonstrated the presence of SUMOylated PGRMC1 primarily in nuclear cell fractions (Sabbir, 2019), and Terzaghi et al (2018) confirmed a nucleolar localization for PGRMC1, where it was responsible for nuclear localization of nucleolin which they proposed was associated with stress response. The zebrafish knockout of PGRMC1 results in elevated levels of mPRα mRNA, but decreased levels of the corresponding protein (Wu et al, 2018), suggesting that PGRMC1 can indeed affect the translational efficiency of certain mRNAs by ribosomes, which is consistent with our pathways analysis results, and especially the principal components analysis of Figure S1A which predicts that ribosomes and translation contributed most to the differences between cells.…”

Identification of Novel MicroRNAs and Characterization of MicroRNA Expression Profiles in Zebrafish Ovarian Follicular Cells

“…We therefore examined 3 genes that play critical roles in LH- and MIH-induced oocyte maturation to determine if they might be regulated by miRNAs differentially expressed in stage IIIa and IIIb cells. Interestingly, we found that two miRNAs predicted to target pgrmc1 , whose knockout or inhibition impaired MIH-induced oocyte maturation (53, 54), were strongly down-regulated in stage IIIb cells. It has been reported that oocytes from follicles ranged from 0.55 to 0.65 mm, which are similar to the stage IIIb follicles used in our study, had much higher pgrmc1 protein levels than oocytes at earlier vitellogenic stages (55).…”

PGRMC Proteins Are Coming of Age: A Special Issue on the Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology

“…Steroid responses are central to reproductive tissues, and PGRMCs are associated with both healthy and cancerous vertebrate reproductive biology. Interestingly, the effects manifest as diversely as the regulation of the spindle-mediated meiotic/mitotic separation of chromosomes, induction of cell and tissue maturation processes, and cancer survival [ 17 , 20 , 22 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”