iScience (Dec 2020)
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
Affiliations
- Livio Casarini
- 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; Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy; Corresponding author
- Clara Lazzaretti
- 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; International PhD School in Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, Modena, Italy
- Elia Paradiso
- 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; International PhD School in Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, Modena, Italy
- Silvia Limoncella
- 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
- Laura Riccetti
- 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
- Samantha Sperduti
- 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; Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy
- Beatrice Melli
- 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
- Serena Marcozzi
- Histology and Embryology Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
- Claudia Anzivino
- 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
- Niamh S. Sayers
- Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
- Jakub Czapinski
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland; Postgraduate School of Molecular Medicine, Warsaw, Poland
- Giulia Brigante
- 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; Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy
- Francesco Potì
- Department of Medicine and Surgery, Unit of Neurosciences, University of Parma, Parma, Italy
- Antonio La Marca
- Mother-Infant Department, University of Modena and Reggio Emilia, Modena, Italy; Clinica EUGIN, Modena, Italy
- Francesco De Pascali
- PRC, INRAE, CNRS, IFCE, Université de Tours, Nouzilly, France
- Eric Reiter
- PRC, INRAE, CNRS, IFCE, Université de Tours, Nouzilly, France
- Angela Falbo
- Department of Obstetrics and Gynaecology, Fertility Center, ASMN. Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Reggio Emilia, Modena, Italy
- Jessica Daolio
- Department of Obstetrics and Gynaecology, Fertility Center, ASMN. Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Reggio Emilia, Modena, Italy
- Maria Teresa Villani
- Department of Obstetrics and Gynaecology, Fertility Center, ASMN. Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Reggio Emilia, Modena, Italy
- Monica Lispi
- International PhD School in Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, Modena, Italy; Global Medical Affair, Merck KGaA, Darmstadt, Germany
- Giovanna Orlando
- Medical Affair, Merck Serono SpA, Rome, Italy
- Francesca G. Klinger
- Histology and Embryology Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
- Francesca Fanelli
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy
- Adolfo Rivero-Müller
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
- Aylin C. Hanyaloglu
- Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
- Manuela Simoni
- 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; Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy; Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy; PRC, INRAE, CNRS, IFCE, Université de Tours, Nouzilly, France
- Journal volume & issue
-
Vol. 23,
no. 12
p. 101812
Abstract
Summary: 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.
