Insulin signaling is an essential regulator of endometrial proliferation and implantation in mice

• Published in: The FASEB journal Vol. 35; no. 4; p. e21440
• Main Authors: Sekulovski, Nikola, Whorton, Allison E, Shi, Mingxin, Hayashi, Kanako, MacLean, 2nd, James A
• Format: Journal Article
• Language: English
• Published: United States 01.04.2021
• Subjects: Animals; Cell-Penetrating Peptides; Embryo Implantation; Endometrium - physiology; Female; Gene Expression Regulation - physiology; Gene Silencing; Insulin - metabolism; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinase Kinases - metabolism; Pregnancy; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Signal Transduction; implantations; insulin signaling; knockout mice; uterus; endometrial proliferation
• ISSN: 1530-6860
• DOI: 10.1096/fj.202002448R

Insulin signaling is critical for the development of preovulatory follicles and progression through the antral stage. Using a conditional knockout model that escapes this blockage, we recently described the role of insulin signaling in granulosa cells during the periovulatory window in mice lacking Insr and Igf1r driven by Pgr-Cre. These mice were infertile, exhibiting defects in ovulation, luteinization, steroidogenesis, and early embryo development. Herein, we demonstrate that while these mice exhibit normal uterine receptivity, uterine cell proliferation and decidualization are compromised resulting in complete absence of embryo implantation in uteri lacking both receptors. While the histological organization of double knockout mice appeared normal, the thickness of their endometrium was significantly reduced. This was supported by the reduced proliferation of both epithelial and stromal cells during the preimplantation stages of pregnancy. Expression and localization of the main drivers of uterine proliferation, ESR1 and PGR, was normal in knockouts, suggesting that insulin signaling acts downstream of these two receptors. While AKT/PI3K signaling was unaffected by insulin receptor ablation, activation of p44/42 MAPK was significantly reduced in both single and double knockout uteri at 3.5 dpc. Overall, we conclude that both INSR and IGF1R are necessary for optimal endometrial proliferation and implantation.