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Regulation of P450c17 expression in the early embryo depends on GATA factors

Yimin Shi1, Marcus D Schonemann, Synthia H Mellon

  • 1Department of Obstetrics, Gynecology, and Reproductive Science, University of California San Francisco, San Francisco, CA 94143-0556, USA.

Endocrinology
|October 4, 2008
PubMed

Insights

Cytochrome P450 17A1 (P450c17) is crucial for steroid biosynthesis. GATA4 and GATA6 transcription factors activate P450c17 gene expression during early mouse embryonic development, particularly in endoderm lineages.

Area of Science:

  • Endocrinology
  • Developmental Biology
  • Molecular Genetics

Background:

  • Cytochrome P450 17A1 (P450c17) is essential for synthesizing glucocorticoids, sex steroids, and neurosteroids.
  • While P450c17 deficiency in humans causes developmental issues, its ablation in mice leads to embryonic lethality, indicating a critical role in early development.
  • Steroidogenic factor-1 (SF-1), vital for adult steroidogenesis, is absent in early mouse embryos, suggesting alternative regulatory mechanisms for embryonic P450c17 expression.

Purpose of the Study:

  • To investigate the expression pattern and regulatory mechanisms of P450c17 during early mouse embryonic development.
  • To identify the transcription factors responsible for activating P450c17 gene expression in embryonic endoderm lineages.

Main Methods:

  • Expression analysis of P450c17 in various mouse cell types, including embryonic stem cells and differentiated endoderm lineages.
  • Reporter assays using the rat cyp17 gene promoter to assess the role of SF-1 and GATA factors.
  • Chromatin immunoprecipitation (ChIP) assays to determine GATA4 binding to the mouse cyp17 gene promoter.
  • Quantitative PCR (qPCR) to measure mRNA levels of GATA4, GATA6, and P450c17 during F9 cell differentiation.
  • Small interfering RNA (siRNA) to inhibit GATA4 and GATA6 function and assess their impact on cyp17 expression.

Main Results:

  • P450c17 is expressed in differentiated mouse parietal and visceral endoderm, embryonic stem cells, and P19 stem cells.
  • The promoter region (-110 to -55) of the rat cyp17 gene, containing GATA sites, confers promoter activity in F9 cells.
  • Overexpression of GATA4, but not SF-1, increased P450c17 transcription and mRNA levels in F9 cells.
  • GATA4 binds to the promoter region (-215/+55) of the mouse cyp17 gene.
  • Cell differentiation induced by retinoic acid and cAMP increased GATA4 and GATA6 mRNA, followed by increased P450c17 mRNA.
  • Inhibition of GATA4 or GATA6 significantly reduced endogenous cyp17 expression in F9 cells.

Conclusions:

  • P450c17 expression is present in mouse embryonic stem cells and up-regulated upon differentiation into early embryonic endoderm lineages.
  • GATA4 and GATA6 are key transcription factors responsible for activating P450c17 gene expression during early embryonic development.
  • These findings elucidate a novel regulatory pathway for P450c17 in embryonic development, distinct from the SF-1 dependent pathway in adults.

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