A cell-autonomous role for WT1 in regulating Sry in vivo

Bradford, Stephen T., Wilhelm, Dagmar, Bandiera, Roberto, Vidal, Valerie, Schedl, Andreas and Koopman, Peter (2009) A cell-autonomous role for WT1 in regulating Sry in vivo. Human Molecular Genetics, 18 18: 3429-3438. doi:10.1093/hmg/ddp283

Author Bradford, Stephen T.
Wilhelm, Dagmar
Bandiera, Roberto
Vidal, Valerie
Schedl, Andreas
Koopman, Peter
Title A cell-autonomous role for WT1 in regulating Sry in vivo
Formatted title
A cell-autonomous role for WT1 in regulating Sry in vivo
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
Publication date 2009-09-01
Year available 2009
Sub-type Article (original research)
DOI 10.1093/hmg/ddp283
Open Access Status Not yet assessed
Volume 18
Issue 18
Start page 3429
End page 3438
Total pages 9
Editor Kay Davies
Anthony Wynshaw-Boris
Joel Hirschhorn
Place of publication Oxford, England, U. K.
Publisher Oxford University Press
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
060403 Developmental Genetics (incl. Sex Determination)
Abstract Human patients with Frasier syndrome express reduced levels of the +KTS isoforms of the developmental regulator WT1 and exhibit complete XY gonadal dysgenesis and male-to-female sex reversal. Mice with a targeted mutation that blocks production of these isoforms show a reduction in Sry mRNA in the gonad, but the molecular and cellular basis of this reduction has not been established. Using immunofluorescence analysis, we found a significantly lower level of SRY protein per cell in XY Wt1(+KTS)-null mouse gonads. We also found a reduced number of SRY-expressing cells, correlating with a decrease in cell proliferation at and near the coelomic epithelium at 11.5 dpc. No reduction in somatic cell numbers was seen in XX Wt1(+KTS)-null gonads, indicating that the effect of WT1 on cell proliferation is mediated by Sry. Sertoli cell differentiation was blocked in XY Wt1(+KTS)-null mouse gonads, as indicated by the loss of SOX9 and Fgf9 expression, but the addition of recombinant FGF9 to ex vivo gonad cultures rescued the mutant phenotype, as indicated by the induction of the Sertoli-cell specific marker anti-Müllerian hormone. Our data suggest that WT1(+KTS) is involved in the cell-autonomous regulation of Sry expression, which in turn influences cell proliferation and Sertoli cell differentiation via FGF9. Thus, sex reversal in Wt1(+KTS)-null mice and Frasier syndrome patients results from a failure of Sertoli cells both to fully differentiate and to reach sufficient numbers to direct testis development.
Keyword Mammalian sex determination
Determining gene sry
Tumour protein WT1
Mouse gonad
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID ANR-05-MRAR-019-01
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
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Created: Fri, 04 Sep 2009, 20:21:33 EST