title: Implantation failure in mice with a disruption in Phospholipase C beta 1 gene: lack of embryonic attachment, aberrant steroid hormone signalling and defective endocannabinoid metabolism.
abstract: Phospholipase C beta 1 (PLCβ1) is a downstream effector of G-protein-coupled receptor signalling and holds central roles in reproductive physiology. Mice with a disruption in the Plcβ1 gene are infertile with pleiotropic reproductive defects, the major reproductive block in females being implantation failure. Here, PLCβ1 was demonstrated at the luminal and glandular epithelia throughout the pre- and peri-implantation period, with transient stromal expression during 0.5-1.5 days post coitum (dpc). Examination of implantation sites at 4.5 dpc showed that in females lacking functional PLCβ1 (knock-out (KO) females), embryos failed to establish proper contact with the uterine epithelium. Proliferating luminal epithelial cells were evident in KO implantation sites, indicating failure to establish a receptive uterus. Real-time PCR demonstrated that KO implantation sites had aberrant ovarian steroid signalling, with high levels of estrogen receptor α, lactoferrin and amphiregulin mRNA, while immunohistochemistry revealed very low levels of estrogen receptor α protein, possibly due to rapid receptor turnover. KO implantation sites expressed markedly less fatty acid amide hydrolase and monoacylglycerol lipase, indicating that endocannabinoid metabolism was also affected. Collectively, our results show that PLCβ1 is essential for uterine preparation for implantation, and that defective PLCβ1-mediated signalling during implantation is associated with aberrant ovarian steroid signalling and endocannabinoid metabolism.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Filis
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kind
authors.forename: Norah
authors.initials: N
authors.lastname: Spears
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D066258:Amphiregulin; D000818:Animals; D066255:EGF Family of Proteins; D010064:Embryo Implantation; D004622:Embryo, Mammalian; D063388:Endocannabinoids / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D045166:Estradiol Congeners / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D007247:Infertility, Female / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007781:Lactoferrin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D054799:Phospholipase C beta / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D014599:Uterus / Q000378:metabolism* / Q000473:pathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D066258:Amphiregulin; D066255:EGF Family of Proteins; D063388:Endocannabinoids; D045166:Estradiol Congeners; D047628:Estrogen Receptor alpha; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007781:Lactoferrin; D008994:Monoacylglycerol Lipases; D054799:Phospholipase C beta; D000099252:Fatty Acid Amide Hydrolases; C587849:Areg protein, mouse; C518034:Plcb1 protein, mouse