TISSUE-SPECIFIC ABLATION OF INSULIN RECEPTOR SIGNALING RESULTS IN INFERTILITY IN FEMALE MICE

Author

Nikola Sekulovski, Southern Illinois University CarbondaleFollow

Date of Award

9-1-2020

Degree Name

Doctor of Philosophy

Department

Molecular, Cellular, and Systemic Physiology

First Advisor

MacLean, James

Abstract

IGF1 and its receptor IGF1R have been correlated with the proliferation of granulosa cells as well as steroid synthesis. Studies have shown that conditional ablation of Igf1r in granulosa cells leads to follicular arrest at a secondary stage, absence of ovulation and infertility. With a high homology between IGF1R and INSR, the full effects of insulin signaling could be masked by just a single receptor knockout. Therefore, utilizing Esr2-iCre we generated a granulosa specific double knockout mouse model. These mice have severely disrupted follicular development, with a block at a primary stage. Granulosa cells do not proliferate, while the oocytes appear activated resulting in reduction of ovarian size, absence of estrous cyclicity and infertility. Since an early granulosa cell knockout leads to block in follicular development, it masks the receptor function during ovulation, and CL formation. With the use of Pgr-Cre, the follicular development goes undisturbed until the periovulatory stages. Pgr-Cre knockout of Insr and Igf1r results in reduced ovulation, and progesterone synthesis. Few oocytes, that do escape, get fertilized but fail to thrive, and do not implant. Pgr-Cre is also active in the uterine endometrium. Ablation of Insr and Igf1r in the uterus results in reduced endometrial proliferation during the preimplantation period, complete absence of implantation and decidualization. Collectively, these results indicate the importance of INSR and IGF1R during follicular development, and ovulation, as well as in uterine proliferation, implantation, and decidualization.