Syncytin 2 is a newly identified placental membrane protein with fusogenic and immunosuppressive activities. Major facilitator superfamily domain containing 2A (MFSD2A) is the cognate receptor for syncytin 2-mediated cell-cell fusion. Both syncytin 2 and MFSD2A are highly expressed in placenta. In this study to understand the regulation of syncytin 2 and MFSD2A expression in placenta, we found that syncytin 2 gene is epigenetically silenced in nonplacental cells by cytosine-phosphate-guanine (CpG) dinucleotide methylation and that expression of syncytin 2 and MFSD2A genes are regulated by the placental transcription factor GCM1 in placental cells. Functional GCM1-binding sites were identified in syncytin 2 and MFSD2A promoters based on electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Because GCM1 activity is decreased in hypoxic placental cells, we further confirmed that expression of MFSD2A is downregulated in hypoxic BeWo choriocarcinoma cells. Interestingly, ectopic expression of GCM1 activated syncytin 2 and MFSD2A expression in MCF-7 breast cancer cells and facilitated MCF-7 cell fusion. The expression of syncytin 2 in MCF-7 cells was partly attributed to CpG demethylation in the syncytin 2 promoter in the presence of GCM1. Our results suggest that GCM1 is a critical factor in controlling placental cell fusion through transcriptional regulation of syncytin 2 and MFSD2A gene expression in placenta. In addition, GCM1 may also play an important role in the epigenetic regulation of syncytin 2 gene expression.
We examined the developmental profile of a kazal-type trypsin inhibitor (P12) of Mr 6126 in mouse seminal vesicle, characterized its binding sites on the surface of sperm, and assessed its effect on Ca2+ uptake by spermatozoa. Among the genital tracts of adult mice, P12 was found only in the male accessory glands including seminal vesicle, coagulating gland, and prostate. It was immunolocalized on the luminal epithelium of the primary and secondary folds in both the seminal vesicle and coagulating gland, and on the folds projecting into the lumen of the glandular alveolus in the prostate. The protein and its RNA message in seminal vesicle did not appear in the prepubertal period, but expression coincided with maturation. Castration of adult mice resulted in cessation of P12 expression. Treatment of the castrated mice with testosterone propionate in corn oil restored the protein expression in the seminal vesicle. Spermatozoa collected from caudal epididymis were devoid of P12. Cytochemical study illustrated a P12-binding region on the anterior acrosomes of cells preincubated with P12. Analysis of equilibrium data from the binding assay using 125I-P12 with a Scatchard plot showed a single type of P12-binding sites on sperm, with an apparent dissociation constant of 70.15 +/- 5.25 nM and the capacity of 1.49 +/- 0.06 x 10(6) binding sites/cell. The protein could serve as a calcium transport inhibitor to suppress a great extent of Ca2+ uptake by spermatozoa. The immunohistochemical staining patterns of testis revealed that the P12-binding sites appeared on postmeiotic cells such as spermatids and spermatozoa, but were absent in Leydig cells, Sertoli cells, spermatogonia, and spermatocytes in seminiferous tubules.
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