FOXL2 transcriptionally represses Sf1 expression by antagonizing WT1 during ovarian development in mice

Takasawa, Kei, Kashimada, Kenichi, Pelosi, Emanuele, Takagi, Masatoshi, Morio, Tomohiro, Asahara, Hiroshi, Schlessinger, David, Mizutani, Shuki and Koopman, Peter (2014) FOXL2 transcriptionally represses Sf1 expression by antagonizing WT1 during ovarian development in mice. The FASEB Journal, Early Edition 5: 1-9. doi:10.1096/fj.13-246108

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Author Takasawa, Kei
Kashimada, Kenichi
Pelosi, Emanuele
Takagi, Masatoshi
Morio, Tomohiro
Asahara, Hiroshi
Schlessinger, David
Mizutani, Shuki
Koopman, Peter
Title FOXL2 transcriptionally represses Sf1 expression by antagonizing WT1 during ovarian development in mice
Formatted title
FOXL2 transcriptionally represses Sf1 expression by antagonizing WT1 during ovarian development in mice
Journal name The FASEB Journal   Check publisher's open access policy
ISSN 0892-6638
Publication date 2014-01-22
Year available 2014
Sub-type Article (original research)
DOI 10.1096/fj.13-246108
Open Access Status Not Open Access
Volume Early Edition
Issue 5
Start page 1
End page 9
Total pages 9
Place of publication Bethesda, MD, United States
Publisher Federation of American Societies for Experimental Biology
Language eng
Abstract Male sex determination in mammals relies on SRY-mediated up-regulation of SOX9 expression in XY gonads, whereas WNT/RSPO signalling and FOXL2 drive female sex determination in XX gonads. FGF9-signalling ensures sustained SOX9 expression through repression of one of the ovarian pathways (WNT signalling), while the significance of FGF-mediated repression of the FOXL2 pathway has not been studied. Previously, we demonstrated that FGFR2 is the receptor for FGF9 in the XY gonad. Whether a specific isoform (FGFR2b or FGFR2c) is required was puzzling. Here, we show that FGFR2c is required for male sex determination. Initially, in developing mouse embryos at 12.5-13.5 days post coitum (dpc), XY Fgfr2c-/- gonads appear ovotestes, with SOX9 and FOXL2 expression predominantly localised to the posterior and anterior gonadal poles, respectively. However by 15.5dpc, XY Fgfr2c-/- gonads show complete male-to-female sex reversal, evident by the lack of SOX9 and ectopic expression of FOXL2 throughout the gonads. Furthermore, ablation of the Foxl2 gene leads to partial or complete rescue of gonadal sex reversal in XY Fgfr2c-/- mice. Together with previous findings, our data suggest that testis determination involves FGFR2c-mediated repression of both the WNT4- and FOXL2-driven ovarian determining pathways.
Formatted abstract
Steroidogenic factor 1 (SF1; Ad4BP/NR5A1) plays key roles in gonadal development. Initially, the Sf1 gene is expressed in mouse fetal gonads of both sexes, but later is up-regulated in testes and down-regulated in ovaries. While Sf1 expression is activated and maintained by Wilms tumor 1 (WT1) and LIM homeobox 9 (LHX9), the mechanism of sex-specific regulation remains unclear. We hypothesized that Sf1 is repressed by the transcription factor Forkhead box L2 (FOXL2) during ovarian development. In an in vitro system (TM3 cells), up-regulation of Sf1 by the WT1 splice variant WT1-KTS was antagonized by FOXL2, as determined by quantitative RT-PCR. Using reporter assays, we localized the Sf1 proximal promoter region involved in this antagonism to a 674-bp interval. A conserved FOXL2 binding site was identified in this interval by in vitro chromatin immunoprecipitation. Introducing mutations into this site abolished negative regulation by FOXL2 in reporter assays. Finally, in Foxl2-null mice, Sf1 expression was increased 2-fold relative to wild-type XX fetal gonads. Our results support the hypothesis that FOXL2 negatively regulates Sf1 expression by antagonizing WT1-KTS during early ovarian development in mice.
Keyword Sex determination
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID R01 DE020823
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 18 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 25 Feb 2014, 23:40:21 EST by Susan Allen on behalf of Institute for Molecular Bioscience