The luteinizing hormone receptor knock-out mouse as a tool to probe the in vivo actions of gonadotropic hormonesreceptors in females

Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.08.11.244467v1?rss=1
Authors: Jonas, K. C., Rivero Muller, A., Oduwole, O., Peltoketo, H., Huhtaniemi, I. T.
Abstract:
Mouse models with altered gonadotropin functions have provided invaluable insight into the functions of these hormones/receptors. Here we describe the repurposing of the infertile and hypogonadal LHR knockout mouse model (LuRKO), to address outstanding questions in reproductive physiology. Using crossbreeding strategies and physiological and histological analyses, we first addressed the physiological relevance of forced LHR homomerization in female mice using BAC expression of two mutant LHR, that have previously shown to undergo functional complementation and rescue the hypogonadal phenotype of male LuRKO mice. In female LuRKO mice, co-expression of signal and binding deficient LHR mutants failed to rescue the hypogonadal and anovulatory phenotype. This was apparently due to the low-level expression of the two mutant LHR and potential lack of LH/LHR-dependent pleiotropic signaling that has previously been shown to be essential for ovulation. Next, we utilized a mouse model overexpressing human chorionic gonadotropin (hCG) with increased circulating LH/hCG-like bioactivity to ~40 fold higher than WT females, to determine if high circulating hCG could reveal putative LHR-independent actions. No effects were found, thus, suggesting that LH/hCG mediate their gonadal and non-gonadal effects solely via LHR. Finally, targeted expression of a constitutively active FSHR progressed antral follicles to pre-ovulatory follicles and displayed phenotypic markers of enhanced estrogenic activity but failed to induce ovulation in LuRKO mice. This study highlights the critical importance and precise control of LHR and FSHR for mediating ovarian functions and of the potential re-purposing existing genetically modified mouse models in answering outstanding physiological questions.
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