Murine FSH Production Depends on the Activin Type II Receptors ACVR2A and ACVR2B

Author:

Schang Gauthier1,Ongaro Luisina1,Schultz Hailey2,Wang Ying1,Zhou Xiang1,Brûlé Emilie2,Boehm Ulrich3,Lee Se-Jin45,Bernard Daniel J12ORCID

Affiliation:

1. Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada

2. Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada

3. Department of Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg, Germany

4. The Jackson Laboratory, Farmington, Connecticut

5. University of Connecticut School of Medicine, Department of Genetics and Genome Sciences, Farmington, Connecticut

Abstract

Abstract Activins are selective regulators of FSH production by pituitary gonadotrope cells. In a gonadotrope-like cell line, LβT2, activins stimulate FSH via the activin type IIA receptor (ACVR2A) and/or bone morphogenetic protein type II receptor (BMPR2). Consistent with these observations, FSH is greatly reduced, though still present, in global Acvr2a knockout mice. In contrast, FSH production is unaltered in gonadotrope-specific Bmpr2 knockout mice. In light of these results, we questioned whether an additional type II receptor might mediate the actions of activins or related TGF-β ligands in gonadotropes. We focused on the activin type IIB receptor (ACVR2B), even though it does not mediate activin actions in LβT2 cells. Using a Cre-lox strategy, we ablated Acvr2a and/or Acvr2b in murine gonadotropes. The resulting conditional knockout (cKO) animals were compared with littermate controls. Acvr2a cKO (cKO-A) females were subfertile (~70% reduced litter size), cKO-A males were hypogonadal, and both sexes showed marked decreases in serum FSH levels compared with controls. Acvr2b cKO (cKO-B) females were subfertile (~20% reduced litter size), cKO-B males had a moderate decrease in testicular weight, but only males showed a significant decrease in serum FSH levels relative to controls. Simultaneous deletion of both Acvr2a and Acvr2b in gonadotropes led to profound hypogonadism and FSH deficiency in both sexes; females were acyclic and sterile. Collectively, these data demonstrate that ACVR2A and ACVR2B are the critical type II receptors through which activins or related TGF-β ligands induce FSH production in mice in vivo.

Funder

Canadian Institutes of Health Research

Natural Sciences and Engineering Research Council of Canada

Fonds de Recherche du Québec—Santé

Publisher

The Endocrine Society

Subject

Endocrinology

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