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Human Molecular Genetics Advance Access originally published online on May 20, 2009
Human Molecular Genetics 2009 18(16):2989-3001; doi:10.1093/hmg/ddp237
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The transcription co-factor CITED2 functions during sex determination and early gonad development

Frank William Buaas1, Pierre Val1,2 and Amanda Swain1,*

1 Section of Gene Function and Regulation, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK 2 Unité Mixte de Recherche CNRS 6247, Clermont Université, 24 avenue des Landais, 63177 Aubiere Cedex, France

* To whom correspondence should be addressed. Tel: +44 207 1535355; Fax: +44 207 1535514; Email: amanda.swain{at}icr.ac.uk

Received February 10, 2009; Accepted May 16, 2009

The early bi-potential mammalian gonad requires the expression of a Y-linked gene, Sry, during a brief window of time to ensure proper testis development. WT1 and its direct target gene Sf1 function during sex determination as well as in the specified testes and ovaries. We have previously shown that the transcription co-factor CITED2 interacts with WT1 to stimulate the expression of Sf1 in the adrenogonadal primordium to ensure adrenal development. We now show through genetic interactions and expression analyses that Cited2 acts in the gonad with Wt1 and Sf1 to increase the expression of Sry levels to attain a critical threshold to efficiently initiate testis development. Reducing the gene dosage of Wt1 or Sf1 in Cited2 mutant gonads was sufficient to produce partial XY sex reversal while full sex reversal was attained in mutants containing a hypomorphic SryPOS allele. A direct correlation was observed between XY sex reversal and reduced expression levels of Sry and Sf1 during sex determination, which indicated that Sry is a downstream target of the CITED2/WT1/SF1 regulatory pathway. Our results provide in vivo evidence for the identification of the first transcription co-factor to function during mammalian sex determination, as part of the WT1/SF1 regulatory mechanism. This highlights the gene dosage sensitivity of the pathway's effect on Sry levels and embryonic gonad development.


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