Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival
Livio Casarini
(1)
,
Clara Lazzaretti
(1)
,
Elia Paradiso
(1)
,
Silvia Limoncella
(1)
,
Laura Riccetti
(1)
,
Samantha Sperduti
(1)
,
Beatrice Melli
(1)
,
Serena Marcozzi
(2)
,
Claudia Anzivino
(1)
,
Niamh S Sayers
(3)
,
Jakub Czapinski
(4)
,
Giulia Brigante
(1)
,
Francesco Potì
(5)
,
Antonio La Marca
(1)
,
Francesco de Pascali
(6)
,
Eric Reiter
(6, 7)
,
Angela Falbo
(8)
,
Jessica Daolio
(8)
,
Maria Teresa Villani
(8)
,
Monica Lispi
(1)
,
Giovanna Orlando
(9)
,
Francesca Klinger
(10)
,
Francesca Fanelli
(1)
,
Adolfo Rivero-Müller
(4)
,
Aylin Hanyaloglu
(3)
,
Manuela Simoni
(1, 6)
1
UNIMORE -
Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia
2 University of Rome "Tor Vergeta"
3 Imperial College London
4 Medical University of Lublin
5 UNIPR - Università degli studi di Parma = University of Parma
6 PRC - Physiologie de la reproduction et des comportements [Nouzilly]
7 MUSCA - Dynamiques de populations multi-échelles pour des systèmes physiologiques
8 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico
9 Merck Research Laboratories
10 Università degli Studi di Roma Tor Vergata [Roma] = University of Rome Tor Vergata
2 University of Rome "Tor Vergeta"
3 Imperial College London
4 Medical University of Lublin
5 UNIPR - Università degli studi di Parma = University of Parma
6 PRC - Physiologie de la reproduction et des comportements [Nouzilly]
7 MUSCA - Dynamiques de populations multi-échelles pour des systèmes physiologiques
8 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico
9 Merck Research Laboratories
10 Università degli Studi di Roma Tor Vergata [Roma] = University of Rome Tor Vergata
Clara Lazzaretti
- Fonction : Auteur
- PersonId : 1082586
Elia Paradiso
- Fonction : Auteur
- PersonId : 1082587
Eric Reiter
- Fonction : Auteur
- PersonId : 743012
- IdHAL : eric-reiter
- ORCID : 0000-0002-4631-7439
- IdRef : 110176251
Résumé
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 Gas protein/cAMP-pathway coupling and FSH responsiveness of patients undergoing controlled ovarian stimulation. In contrast, FSHR/GPER heteromer striggered anti-apoptotic/proliferative FSH signaling delivered via the Gbgdimer, where as 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