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

Kenichi Kashimada, Terje Svingen, Chun-Wei Feng, Emanuele Pelosi, Stefan Bagheri-Fam, Vincent R. Harley, David Schlessinger, Josephine Bowles, Peter Koopman

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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 similar to 20-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.-Kashimada, K., Svingen, T., Feng, C.-W., Pelosi, E., Bagheri-Fam, S., Harley, V. R., Schlessinger, D., Bowles, J., Koopman, P. Antagonistic regulation of Cyp26b1 by transcription factors SOX9/SF1 and FOXL2 during gonadal development in mice. FASEB J. 25, 3561-3569 (2011).
Original languageEnglish
JournalF A S E B Journal
Issue number10
Pages (from-to)3561-3569
Number of pages9
Publication statusPublished - 2011
Externally publishedYes


  • CELL
  • Forkhead box protein L2
  • germ cells
  • meiosis
  • retinoic acid
  • sex determination
  • Rodentia Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates) - Muridae [86375] mouse common embryo female, male transgenic, C57B6/J/129/SVJ, strain-C57BL/6, strain-Swiss Quack, strain-CD1 TM3 cell line cell_line mouse gonadal somatic cells
  • mouse Cyp26b1 gene [Muridae] expression, up-regulation
  • mouse Foxl2 gene [Muridae] mutation
  • mouse Sf1 gene [Muridae] mouse steroidogenic factor-1 gene expression
  • mouse Sox9 gene [Muridae] mouse Sry-related HMGbox 9 gene expression
  • Forkhead box L2
  • retinoic acid 302-79-4
  • 02506, Cytology - Animal
  • 03502, Genetics - General
  • 03506, Genetics - Animal
  • 10066, Biochemistry studies - Lipids
  • 16504, Reproductive system - Physiology and biochemistry
  • 17002, Endocrine - General
  • 17006, Endocrine - Gonads and placenta
  • 25502, Development and Embryology - General and descriptive
  • Development
  • Molecular Genetics
  • Reproductive System
  • gonadal development
  • XX-karyotype
  • Biochemistry and Molecular Biophysics
  • Reproduction
  • germ cell reproductive system
  • gonad reproductive system, endocrine system
  • Leydig cell reproductive system
  • ovary reproductive system
  • Sertoli cell reproductive system
  • testis reproductive system
  • in situ hybridization laboratory techniques, genetic techniques
  • quantitative RT-PCR laboratory techniques, genetic techniques
  • transfection laboratory techniques, genetic techniques
  • Animals
  • Cytochrome P-450 Enzyme System
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Developmental
  • Male
  • Mice
  • SOX9 Transcription Factor
  • Sex Determination Processes
  • Testis
  • Transcription Factors
  • Up-Regulation
  • Foxl2 protein, mouse
  • Sox9 protein, mouse
  • Zfp162 protein, mouse
  • 9035-51-2 Cytochrome P-450 Enzyme System
  • EC retinoic acid 4-hydroxylase
  • cytochrome P450 26B1
  • steroidogenic factor 1
  • transcription factor
  • transcription factor FOXL2
  • transcription factor Sox9
  • unclassified drug
  • animal experiment
  • article
  • controlled study
  • embryo
  • enzyme regulation
  • gene activation
  • gene control
  • gene expression
  • genetic transfection
  • germ cell
  • gonad development
  • high mobility group box domain
  • hypothesis
  • in situ hybridization
  • Leydig cell
  • male
  • mouse
  • nonhuman
  • priority journal
  • rat
  • real time polymerase chain reaction
  • Sertoli cell
  • somatic cell
  • testis
  • upregulation
  • wild type
  • Mus
  • Germ cells
  • Meiosis
  • Retinoic acid
  • Sex determination


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