Human follicle-stimulating hormone β subunit expression depends on FOXL2 and SMAD4

Item Type:	Article
Title:	Human follicle-stimulating hormone β subunit expression depends on FOXL2 and SMAD4
Creators Name:	Ongaro, L. and Schang, G. and Zhou, Z. and Kumar, T.R. and Treier, M. and Deng, C.X. and Boehm, U. and Bernard, D.J.
Abstract:	Follicle-stimulating hormone (FSH), an essential regulator of mammalian fertility, is synthesized by pituitary gonadotrope cells in response to activins. In mice, activins signal via SMAD3, SMAD4, and FOXL2 to regulate transcription of the FSHβ subunit (Fshb) gene. Gonadotrope-specific deletion of Foxl2, alone or in combination with Smad4, renders mice FSH-deficient. Whether human FSHB expression is similarly regulated is not known. Here, we used a combination of transgenic and conditional knockout mouse strains to assess the roles of activins, FOXL2, and SMAD4 in regulation of the human FSHB gene. First, we cultured pituitaries from mice harboring a human FSHB transgene (hFSHB mice) and measured both murine Fshb and human FSHB mRNA expression in response to exogenous activins or two antagonists of endogenous activin-like signaling (follistatin-288 and SB431542). Both murine Fshb and human FSHB expression were stimulated by activins and reduced by the inhibitors. Next, we analyzed human FSHB expression in hFSHB mice carrying floxed Foxl2 and Smad4 alleles. Cre-mediated ablation of FOXL2 and SMAD4 strongly reduced basal and activin-stimulated murine Fshb and human FSHB expression in cultured pituitaries. Finally, the hFSHB transgene was previously shown to rescue FSH production and fertility in Fshb knockout mice. However, gonadotrope-specific Foxl2/Smad4 knockout females carrying the hFSHB transgene have significantly reduced murine Fshb and human FSHB pituitary mRNA levels and are hypogonadal. Collectively, these data suggest that similar to Fshb regulation in mice, FOXL2 and SMAD4 play essential roles in human FSHB expression.
Keywords:	FSH, Transgene, Gonadotrope, Activin, Pituitary, FOXL2, SMAD4, Animals, Mice
Source:	Endocrinology
ISSN:	0013-7227
Publisher:	Endocrine Society
Volume:	161
Number:	5
Page Range:	bqaa045
Date:	May 2020
Additional Information:	Copyright © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
Official Publication:	https://doi.org/10.1210/endocr/bqaa045
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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