title: Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility.
abstract: In mammalian reproduction, implantation is one of the most critical events. Failure of implantation and the subsequent decidualization contribute to more than 75% of pregnancy losses in women. Our laboratory has previously reported that inhibition of Notch signaling results in impaired decidualization in both women and a transgenic mouse model. In this study, we generated a Notch gain-of-function transgenic mouse by conditionally overexpressing the Notch1 intracellular domain (N1ICD) in the reproductive tract driven by a progesterone receptor (Pgr) -Cre. We show that the overexpression of N1ICD in the uterus results in complete infertility as a consequence of multiple developmental and physiological defects, including the absence of uterine glands and dysregulation of progesterone and estrogen signaling by a Recombination Signal Binding Protein Jκ-dependent signaling mechanism. We further show that the inhibition of progesterone signaling is caused by hypermethylation of its receptor Pgr by Notch1 overexpression through the transcription factor PU.1 and DNA methyltransferase 3b (Dnmt3b). We have generated a mouse model to study the consequence of increased Notch signaling in female reproduction and provide the first evidence, to our knowledge, that Notch signaling can regulate epigenetic modification of the Pgr.
authors: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI 49503;
authors: Ren-Wei
authors: RW
authors: Su
authors: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI 49503;
authors: Michael R
authors: MR
authors: Strug
authors: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI 49503; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49503;
authors: Jae-Wook
authors: JW
authors: Jeong
authors: Department of Genetics, Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, New Orleans, LA 70112.
authors: Lucio
authors: L
authors: Miele
authors: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI 49503; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49503; asgi@hc.msu.edu.
authors: Asgerally T
authors: AT
authors: Fazleabas
mesh_terms: D000818:Animals; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007247:Infertility, Female / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014599:Uterus / Q000378:metabolism* / Q000473:pathology
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D011374:Progesterone; D004958:Estradiol
keywords: Notch1; Pgr; infertility; methylation; mouse uterus