Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 8; pp. 2300 - 2305
• Main Authors: Su, Ren-Wei, Strug, Michael R., Jeong, Jae-Wook, Miele, Lucio, Fazleabas, Asgerally T.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23-02-2016; National Acad Sciences
• Subjects: Animals; Biological Sciences; Disease Models, Animal; DNA Methylation; Epigenesis, Genetic; Epigenetics; Estradiol - metabolism; Female; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein - deficiency; Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics; Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism; Infertility, Female - etiology; Infertility, Female - genetics; Infertility, Female - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Pregnancy; Progesterone; Progesterone - metabolism; Promoter Regions, Genetic; Protein expression; Protein Structure, Tertiary; Receptor, Notch1 - chemistry; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Reproduction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Up-Regulation; Uterus - metabolism; Uterus - pathology; Pgr; infertility; Notch1; methylation; mouse uterus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1520441113

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.