Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival

Livio Casarini; Clara Lazzaretti; Elia Paradiso; Silvia Limoncella; Laura Riccetti; Samantha Sperduti; Beatrice Melli; Serena Marcozzi; Claudia Anzivino; Niamh S Sayers; Jakub Czapinski; Giulia Brigante; Francesco Potì; Antonio La Marca; Francesco De Pascali; Eric Reiter; Angela Falbo; Jessica Daolio; Maria Teresa Villani; Monica Lispi; Giovanna Orlando; Francesca G Klinger; Francesca Fanelli; Adolfo Rivero-Müller; Aylin C Hanyaloglu; Manuela Simoni

doi:10.1016/j.isci.2020.101812

Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival

iScience. 2020 Nov 18;23(12):101812. doi: 10.1016/j.isci.2020.101812. eCollection 2020 Dec 18.

Authors

Livio Casarini^{1

2}, Clara Lazzaretti^{1

3}, Elia Paradiso^{1

3}, Silvia Limoncella¹, Laura Riccetti¹, Samantha Sperduti^{1

2}, Beatrice Melli¹, Serena Marcozzi⁴, Claudia Anzivino¹, Niamh S Sayers⁵, Jakub Czapinski^{6

7}, Giulia Brigante^{1

8}, Francesco Potì⁹, Antonio La Marca^{10

11}, Francesco De Pascali¹², Eric Reiter¹², Angela Falbo¹³, Jessica Daolio¹³, Maria Teresa Villani¹³, Monica Lispi^{3

14}, Giovanna Orlando¹⁵, Francesca G Klinger⁴, Francesca Fanelli^{16

17}, Adolfo Rivero-Müller⁶, Aylin C Hanyaloglu⁵, Manuela Simoni^{1

2

8

12}

Affiliations

¹ Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Ospedale Civile Sant'Agostino-Estense, Via P. Giardini 1355, 41126 Modena, Italy.
² Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy.
³ International PhD School in Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, Modena, Italy.
⁴ Histology and Embryology Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
⁵ Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.
⁶ Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.
⁷ Postgraduate School of Molecular Medicine, Warsaw, Poland.
⁸ Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.
⁹ Department of Medicine and Surgery, Unit of Neurosciences, University of Parma, Parma, Italy.
¹⁰ Mother-Infant Department, University of Modena and Reggio Emilia, Modena, Italy.
¹¹ Clinica EUGIN, Modena, Italy.
¹² PRC, INRAE, CNRS, IFCE, Université de Tours, Nouzilly, France.
¹³ Department of Obstetrics and Gynaecology, Fertility Center, ASMN. Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Modena, Italy.
¹⁴ Global Medical Affair, Merck KGaA, Darmstadt, Germany.
¹⁵ Medical Affair, Merck Serono SpA, Rome, Italy.
¹⁶ Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
¹⁷ Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.

Abstract

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.

Keywords: Endocrine Regulation; Female Reproductive Endocrinology; Molecular Biology.