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Pleotropism of Gonadotropin Action Manuela Simoni, Elia Paradiso, Véronique Lockhart, Eric Reiter, Livio Casarini, Lucie P

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Pleotropism of Gonadotropin Action Manuela Simoni, Elia Paradiso, Véronique Lockhart, Eric Reiter, Livio Casarini, Lucie P Pleotropism of gonadotropin action Manuela Simoni, Elia Paradiso, Véronique Lockhart, Eric Reiter, Livio Casarini, Lucie P. Pellissier, Pascale Crépieux To cite this version: Manuela Simoni, Elia Paradiso, Véronique Lockhart, Eric Reiter, Livio Casarini, et al.. Pleotropism of gonadotropin action. 2020, 10.34846/le-studium.194.02.fr.03-2020. hal-03219243 HAL Id: hal-03219243 https://hal.archives-ouvertes.fr/hal-03219243 Submitted on 6 May 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. LE STUDIUM Multidisciplinary Journal www.lestudium-ias.com FELLOWSHIP FINAL REPORT Pleotropism of gonadotropin action Manuela Simoni1,2,3, Elia Paradiso1, Véronique Lockhart2, Eric Reiter2, Livio Casarini1, Lucie Pellissier2, Pascale Crépieux2 1Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy; BIOS group, 2Institute of Physiology of Reproduction and Behavior, INRAe Centre de Recherches Val de Loire, Nouzilly, France 3LE STUDIUM Institute for Advanced Studies, 45000 Orléans, France REPORT INFO ABSTRACT Fellow: Manuela Simoni Evidence exists that the gonadotropins LH and FSH can substitute to each From University of Modena and other under certain circumstances, in addition to the fact that they can act Reggio Emilia, Italy together in granulosa cells. The aim of this study is to investigate how the Host laboratory in region Centre-Val two human gonadotropins influence each other in granulosa cells de Loire: BIOS group, Institute of expressing both receptors, or by co-culturing cells expressing either the Physiology of Reproduction and Behavior, INRAe Centre de LHCGR or the FSHR (as a model granulosa/theca interaction). Plasmids Recherches Val de Loire, 37380 encoding the c-myc-tagged-LHCGR and the FLAG-tagged FSHR under Nouzilly the control of an inducible coumermycin-responsive or doxycycline- Host scientist: Pascale Crépieux responsive promoter, respectively were produced. These plasmids were Period of residence in region Centre- used to permanently transfect human granulosa cell-derived KGN cells Val de Loire: April 8, 2019 – April 7, and HEK293 cells. The following cell lines were obtained and partially 2020 characterized: #1 c-myc-tagged-LHCGR-KGN; #2 FLAG-tagged FSHR_HEK293; #3 FLAG-tagged FSHR-KGN; #4 Double, c-myc- Keywords : tagged-LHCGR and FLAG-tagged FSHR-KGN. After induction of Gonadotropin action, FSHR, LH, receptor expression, the cell lines #1 and #2 and #3 responded to hCG and FSH, Granulosa cells, infertility FSH stimulation, respectively by producing cAMP. Receptor expression was demonstrated by RT-PCR and flow cytometry. The characterization of the cell line #4 is ongoing. These cell lines are now available for the study of cell signaling and steroid synthesis, as well as in silico modeling, to gain insight into the dynamics of the intertwined cell response to FSH and LH in granulosa cells. These experiments will continue in parallel in both laboratories involved. Our cell lines represent new, very valuable instruments for the study of molecular pharmacology of FSH and LH, in order to improve infertility treatment, (multi)follicular growth for assisted reproduction, ovulation and spermatogenesis. 1- Introduction gonadotropins are growth and differentiation factors, modulating cell proliferation, survival The gonadotropins LH and FSH are necessary and apoptosis. The interplay between the two to ensure steroidogenesis, gametogenesis and gonadotropins FSH and LH is complex and reproduction. In primates, a third gonadotropin, several in vitro and in vivo models have hCG, acts during pregnancy via the same demonstrated that, under certain circumstances, receptor for LH, the LHCGR, to stimulate the lack of one of the two can, at least in part, progesterone production by the corpus luteum be compensated for by the other, especially in and maintain pregnancy. The main action of LH the murine species and especially in the case of is to produce testosterone (in both sexes), of spermatogenesis (1). LH and FSH work hCG to produce progesterone (in pregnancy) together to support follicular growth and the and of FSH to produce gametes. In addition, receptors for the two hormones are co- Simoni, M.; Paradiso, E.; Lockhart, V.; Reiter, E.; Casarini, L.; Pellissier, L.; Crépieux, P.; Pleotropism of gonadotropin action, LE STUDIUM Multidisciplinary Journal, 2020, 4, 1-7 https://doi.org/10.34846/le-studium.194.02.fr.03-2020 1 expressed on the same granulosa cells at late Construction of plasmids encoding the c-myc- maturation stages. Since both hormones tagged-LHCGR and the FLAG-tagged FSHR stimulate essentially the same signal under the control of an inducible coumermycin- transduction pathways, the question arises why responsive or doxycycline-responsive are they both necessary and how can the cell promoter; 2) Production of human granulosa differentiate between the two when expressing cell-derived KGN cells and HEK293 cells both receptors. In addition, what is the permanently expressing the inducible c-myc- mechanism by which one gonadotropin can take tagged-LHCGR and the FLAG-tagged FSHR; over the action of the other in certain 3) partial characterization of cell lines obtained. circumstances is unknown. Clinical examples 2.1 Plasmids thereof are the maintenance of spermatogenesis in the absence of FSH (2), but also by FSH The human FSHR, human LHCG or Luciferase activity alone (3), or multiple follicular growth (positive transfection control) mRNA were and maturation in cycles of assisted cloned into EcoRI-XhoI restriction sites of the reproduction (ART) in which only FSH is used pSBtet expression system. The empty vector after profound pituitary down regulation by was used as negative control. The plasmids GnRH analogs. The picture is further were amplified in DH5α E. Coli (New England complicated by the fact that, clinically, hCG is BioLabs, ref C2527H). traditionally used to provide LH action in therapy, while we now know that LH and hCG exert different action on the same receptor (4, The vector includes: a response element 5). In addition, in human granulosa cells, FSH activated by the Tet-sensitive transactivator potentiates the hCG-dependent steroidogenic (activated by doxycycline), the TRE minimal and pro-apoptotic signals while enhancing the promoter, the cDNA of interest (FSHR or potency of LH-dependent proliferative and anti- LHCG), green fluorescent protein (GFP), apoptotic signals exerted through pERK1/2 and Puromycin resistance, Ampicillin resistance. pAKT, resulting in higher cell viability Control plasmids contain, downstream of the compared to FSH and hCG co-treatment (6). inducible promoter, either luciferase or no In the growing follicle of the pre-antral, antral cDNA (negative control). and terminal stages, the action of FSH The FSHR and LHCGR cDNA are N- predominates to promote granulosa cell terminally tagged with FLAG or c-myc, proliferation, until the FSH-induced expression respectively, to allow immune-recognition (in of the LHCGR reaches a defined level of flow cytometry). Four vectors were obtained, expression. Thereafter, the expression level of encoding the c-myc-tagged-LHCGR and the the FSHR drops and cells of the follicle FLAG-tagged FSHR under the control of an continue its growth process, which culminates inducible coumermycin-responsive or with ovulation. This study intends to investigate doxycycline-responsive promoter, respectively. the molecular mechanism of LH/hCG and FSH, action alone and in combination, in a 2.2 Cell lines homologous cell system. In particular, in this Cell lines were obtained starting from the KGN project, we produced some novel human cells (21), a steroidogenic human granulosa cell granulosa cell-derived, KGN cell lines line in which the endogenous FSHR is not conditionally expressing the LHCGR or/and the expressed, and from HEK293 cells (human FSHR embryonic kidney derivation). The HEK293 WT3, obtained previously and permanently expressing the human FLAG-FSHR was used 2- Materials and Methods as positive control. The experimental procedures carried out during Cells were cultured in DMEM (Eurobio ref the fellowship at the host lab included: 1) CM1DME60-01) containing NaHCO3 and Simoni, M.; Paradiso, E.; Lockhart, V.; Reiter, E.; Casarini, L.; Pellissier, L.; Crépieux, P.; Pleotropism of gonadotropin action, LE STUDIUM Multidisciplinary Journal, 2020, 4, 1-7 https://doi.org/10.34846/le-studium.194.02.fr.03-2020 2 glucose, 1% Glutamine (Eurobio, ref 2.5 measurement of cAMP CSTGLU01-0U), 1% of antibiotics Penicillin Intracellular cAMP levels were measured using and Streptomycin (Gibco, ref 15140-122) a homogeneous time-resolved fluorescence 10,000 U / mL, and 10% of SVF (Eurobio, ref: (HTRF ®) cAMP dynamic 2 assay kit (CisBio CVFSVF06-01). Transfected cells were Bioassays, Bagnol sur Cèze, France), as cultured in SVF without tetracycline, called described in (23). Forty-eight hours post- "tet-free" (Ozyme, ref: 631106) in order not to transfection cells were detached and seeded into induce the Tet system unintentionally. white 384-well
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