University of Oulu

Jonas, K. C., Rivero Müller, A., Oduwole, O., Peltoketo, H., & Huhtaniemi, I. (2021). The Luteinizing Hormone Receptor Knockout Mouse as a Tool to Probe the In Vivo Actions of Gonadotropic Hormones/Receptors in Females. Endocrinology, 162(5). https://doi.org/10.1210/endocr/bqab035

The luteinizing hormone receptor knockout mouse as a tool to probe the in vivo actions of gonadotropic hormones/receptors in females

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Author: Jonas, Kim Carol1,2; Müller, Adolfo Rivero3,4; Oduwole, Olayiwola2;
Organizations: 1Department of Women and Children’s Health, King’s College London, London SE1 1UL, UK
2Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
3Institute for Biomedicine, Department of Physiology, University of Turku, 20520 Turku, Finland
4Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland
5Laboratory of Cancer Genetics and Tumour Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu and University of Oulu, 90220 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021043028107
Language: English
Published: Endocrine Society, 2021
Publish Date: 2021-04-30
Description:

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 luteinizing hormone receptor (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 2 ligand-binding and signaling deficient mutant LHR, respectively, that have previously shown to undergo functional complementation and rescue the hypogonadal phenotype of male LuRKO mice. In female LuRKO mice, coexpression of signaling and binding deficient LHR mutants failed to rescue the hypogonadal and anovulatory phenotype. This was apparently due to the low-level expression of the 2 mutant LHR and potential lack of luteinizing hormone (LH)/LHR-dependent pleiotropic signaling that has previously been shown at high receptor densities 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 in the LuRKO background 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 follicle stimulating hormone receptor (FSHR) progressed antral follicles to preovulatory 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 functional LHR and FSHR for mediating ovarian functions and of the potential repurposing of existing genetically modified mouse models in answering outstanding questions in reproductive physiology.

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Series: Endocrinology
ISSN: 0013-7227
ISSN-E: 1945-7170
ISSN-L: 0013-7227
Volume: 162
Issue: 5
Pages: 1 - 13
DOI: 10.1210/endocr/bqab035
OADOI: https://oadoi.org/10.1210/endocr/bqab035
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: Biotechnology and Biological Sciences Research Council grant number BB/1008004/1 and Wellcome Trust grant number 082101/Z/07/Z to IH.
Dataset Reference: Some or all data generated or analyzed during this study are included in this published article or in the data repositories listed in References.
Copyright information: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
  https://creativecommons.org/licenses/by/4.0/