Antagonistic regulation of Cyp26b1 by transcription factors SOX9/SF1 and FOXL2 during gonadal development in mice

Kashimada, Kenichi, Svingen, Terje, Feng, Chun-Wei, Pelosi, Emanuele, Bagheri-Fam, Stefan, Harley, Vincent R., Schlessinger, David, Bowles, Josephine and Koopman, Peter (2011) Antagonistic regulation of Cyp26b1 by transcription factors SOX9/SF1 and FOXL2 during gonadal development in mice. The FASEB Journal, 25 10: 3561-3569. doi:10.1096/fj.11-184333

Author Kashimada, Kenichi
Svingen, Terje
Feng, Chun-Wei
Pelosi, Emanuele
Bagheri-Fam, Stefan
Harley, Vincent R.
Schlessinger, David
Bowles, Josephine
Koopman, Peter
Title Antagonistic regulation of Cyp26b1 by transcription factors SOX9/SF1 and FOXL2 during gonadal development in mice
Formatted title
Antagonistic regulation of Cyp26b1 by transcription factors SOX9/SF1 and FOXL2 during gonadal development in mice
Journal name The FASEB Journal   Check publisher's open access policy
ISSN 0014-9446
Publication date 2011-10-14
Year available 2011
Sub-type Article (original research)
DOI 10.1096/fj.11-184333
Open Access Status DOI
Volume 25
Issue 10
Start page 3561
End page 3569
Total pages 9
Place of publication Bethesda, MD, U.S.A.
Publisher Federation of American Societies for Experimental Biology
Language eng
Subject 1305 Biotechnology
1303 Biochemistry
1312 Molecular Biology
1311 Genetics
Abstract Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancers were able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway-deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.
Formatted abstract
Sex determination in fetal germ cells depends on a balance between exposure to retinoic acid (RA) and the degradation of RA achieved by the testis-specific expression of the catabolic cytochrome P450 enzyme, CYP26B1. Therefore, identification of factors regulating the expression of the Cyp26b1 gene is an important goal in reproductive biology. We used in situ hybridization to demonstrate that Cyp26b1 and transcription factor genes steroidogenic factor-1 (Sf1) and Sry-related HMG box 9 (Sox9) are coexpressed in Sertoli cells, whereas Cyp26b1 and Sf1 are coexpressed in Leydig cells in mouse fetal testes. In the mouse gonadal somatic cell line TM3, transfection of constructs expressing SOX9 and SF1 activated Cyp26b1 expression, independently of the positive regulator RA. In embryonic gonads deficient in SOX9 or SF1, Cyp26b1 expression was decreased relative to wild-type (WT) controls, as measured by quantitative RT-PCR (qRT-PCR). Furthermore, qRT-PCR showed that Cyp26b1 up-regulation by SOX9/SF1 was attenuated by the ovarian transcription factor Forkhead box L2 (FOXL2) in TM3 cells, whereas in Foxl2-null mice, Cyp26b1 expression in XX gonads was increased ≂⃒f20-fold relative to WT controls. These data support the hypothesis that SOX9 and SF1 ensure the male fate of germ cells by up-regulating Cyp26b1 and that FOXL2 acts to antagonize Cyp26b1 expression in ovaries.
Keyword Forkhead box protein L2
Germ cells
Retinoic acid
Sex determination
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published ahead of print July 14, 2011

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 41 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 16 Sep 2011, 22:00:32 EST by Dr Terje Svingen on behalf of Institute for Molecular Bioscience