TY - JOUR
T1 - Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival
AU - Casarini, Livio
AU - Lazzaretti, Clara
AU - Paradiso, Elia
AU - Limoncella, Silvia
AU - Riccetti, Laura
AU - Sperduti, Samantha
AU - Melli, Beatrice
AU - Marcozzi, Serena
AU - Anzivino, Claudia
AU - Sayers, Niamh S.
AU - Czapinski, Jakub
AU - Brigante, Giulia
AU - Potì, Francesco
AU - La Marca, Antonio
AU - De Pascali, Francesco
AU - Reiter, Eric
AU - Falbo, Angela
AU - Daolio, Jessica
AU - Villani, Maria Teresa
AU - Lispi, Monica
AU - Orlando, Giovanna
AU - Klinger, Francesca G.
AU - Fanelli, Francesca
AU - Rivero-Müller, Adolfo
AU - Hanyaloglu, Aylin C.
AU - Simoni, Manuela
N1 - Funding Information:
This study was supported by the Italian Ministry of University and Research (MIUR). M.S. is an LE STUDIUM RESEARCH FELLOW, Loire Valley Institute for Advanced Studies, Orl?ans & Tours, France, - INRA - Center Val de Loire, 37380 Nouzilly, France, receiving funding from the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska-Curie grant agreement No 665790. We would like to thank Dr Andreas Bruckbauer at the Facility for Imaging of Light Microscopy (FILM), Imperial College London, for technical support with PALM. A.C.H. was supported by grants from the BBSRC (BB/1008004/1) and Genesis Research Trust, N.S.S is supported by an Imperial College London President's Scholarship. Grant ?Departments of Excellence Program? from MIUR to the Department of Biomedical, Metabolic and Neural Sciences (University of Modena and Reggio Emilia). Polish National Science Centre (NCN) grants: DEC-2015/17/B/NZ1/01777, DEC-2017/25/B/NZ4/02364. LC designed the study, managed experiments, performed data analysis and interpretation, and wrote the manuscript. CL, EP, SL, and LR performed BRET and western blotting experiments and data analysis. SS, and BM performed BRET and gene expression analysis. SM did immunostainings. CA performed gene expression analysis. NSS have applied the PALM method. JC created the CRISP/Cas9-modified cells. GB, FP, ALM, and MTV provided scientific support, primary cells and tissues, and manuscript editing. ML and GO provided scientific support, data interpretation, and manuscript editing. FGK was involved in the management of immunostainings and manuscript editing. FF did bioinformatics analyzes, data interpretation, and manuscript editing. ARM managed CRISPR/Cas9 experiments, supported data analysis, and did manuscript editing. ACH supported experiments and study design, provided data interpretation, scientific support, and manuscript writing. MS provided study and scientific management, data interpretation, and manuscript writing. ML and GO are Merck Serono SpA employees without any conflict of interest.
Publisher Copyright:
© 2020 The Author(s)
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/18
Y1 - 2020/12/18
N2 - Classically, follicle-stimulating hormone receptor (FSHR)-driven cAMP-mediated signaling boosts human ovarian follicle growth and oocyte maturation. However, contradicting in vitro data suggest a different view on physiological significance of FSHR-mediated cAMP signaling. We found that the G-protein-coupled estrogen receptor (GPER) heteromerizes with FSHR, reprogramming cAMP/death signals into proliferative stimuli fundamental for sustaining oocyte survival. In human granulosa cells, survival signals are missing at high FSHR:GPER ratio, which negatively impacts follicle maturation and strongly correlates with preferential Gαs protein/cAMP-pathway coupling and FSH responsiveness of patients undergoing controlled ovarian stimulation. In contrast, FSHR/GPER heteromers triggered anti-apoptotic/proliferative FSH signaling delivered via the Gβγ dimer, whereas impairment of heteromer formation or GPER knockdown enhanced the FSH-dependent cell death and steroidogenesis. Therefore, our findings indicate how oocyte maturation depends on the capability of GPER to shape FSHR selective signals, indicating hormone receptor heteromers may be a marker of cell proliferation.
AB - Classically, follicle-stimulating hormone receptor (FSHR)-driven cAMP-mediated signaling boosts human ovarian follicle growth and oocyte maturation. However, contradicting in vitro data suggest a different view on physiological significance of FSHR-mediated cAMP signaling. We found that the G-protein-coupled estrogen receptor (GPER) heteromerizes with FSHR, reprogramming cAMP/death signals into proliferative stimuli fundamental for sustaining oocyte survival. In human granulosa cells, survival signals are missing at high FSHR:GPER ratio, which negatively impacts follicle maturation and strongly correlates with preferential Gαs protein/cAMP-pathway coupling and FSH responsiveness of patients undergoing controlled ovarian stimulation. In contrast, FSHR/GPER heteromers triggered anti-apoptotic/proliferative FSH signaling delivered via the Gβγ dimer, whereas impairment of heteromer formation or GPER knockdown enhanced the FSH-dependent cell death and steroidogenesis. Therefore, our findings indicate how oocyte maturation depends on the capability of GPER to shape FSHR selective signals, indicating hormone receptor heteromers may be a marker of cell proliferation.
KW - Endocrine Regulation
KW - Female Reproductive Endocrinology
KW - Molecular Biology
UR - http://www.scopus.com/inward/record.url?scp=85097368513&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097368513&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101812
DO - 10.1016/j.isci.2020.101812
M3 - Article
AN - SCOPUS:85097368513
VL - 23
JO - iScience
JF - iScience
SN - 2589-0042
IS - 12
M1 - 101812
ER -