The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells.

Adrien Georges,Bérangère Legois,Reiner A Veitia,Anne Laure Todeschini,Alain Zider,David L'Hôte,Aurélie Auguste

doi:10.7554/elife.04207

Adrien Georges, Bérangère Legois + Show 5 more

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https://doi.org/10.7554/elife.04207

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Abstract

FOXL2 is a lineage determining transcription factor in the ovary, but its direct targets and modes of action are not fully characterized. In this study, we explore the targets of FOXL2 and five nuclear receptors in murine primary follicular cells. We found that FOXL2 is required for normal gene regulation by steroid receptors, and we show that estrogen receptor beta (ESR2) is the main vector of estradiol signaling in these cells. Moreover, we found that FOXL2 directly modulates Esr2 expression through a newly identified intronic element. Interestingly, we found that FOXL2 repressed the testis-determining gene Sox9 both independently of estrogen signaling and through the activation of ESR2 expression. Altogether, we show that FOXL2 mobilizes estrogen signaling to establish a coherent feed-forward loop repressing Sox9. This sheds a new light on the role of FOXL2 in ovarian maintenance and function.

Highlights

FOXL2 is a key transcriptional regulator of the differentiation and maintenance of granulosa cells, those supporting oocyte maturation and growth during folliculogenesis (Schmidt et al, 2004; Uhlenhaut et al, 2009; Georges et al, 2014)
Our results provide a considerable number of direct and indirect targets of FOXL2 and of various nuclear receptor (NR) in follicular cells, but shows above all how FOXL2 may establish estrogen signaling in the ovary
We show that FOXL2 is essential for Activin-dependent up-regulation of Esr2 in follicular cells

Summary

Introduction

FOXL2 is a key transcriptional regulator of the differentiation and maintenance of granulosa cells, those supporting oocyte maturation and growth during folliculogenesis (Schmidt et al, 2004; Uhlenhaut et al, 2009; Georges et al, 2014). Mature granulosa cells are absent in Foxl2−/− mice because pre-granulosa cells remain blocked and do not undergo further differentiation (Schmidt et al, 2004). FOXL2 heterozygous mutations are responsible for the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), characterized by facial malformations often associated with primary ovarian insufficiency (POI) (Crisponi et al, 2001). Recent works have shown that FOXL2 mutations impairing its DNA binding and/or transcriptional activity are responsible for POI occurrence in BPES (Dipietromaria et al, 2009; Todeschini et al, 2011). A specific somatic mutation of FOXL2 has been identified in more than 95% of adult-type granulosa cell tumors (GCTs) confirming the strong association of FOXL2 with granulosa cell fate and function (Shah et al, 2009; Jamieson and Fuller, 2012)

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