Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left-right patterning defects -- Bentham et al., 10.1093/hmg/ddq251 -- Human Molecular Genetics

Human Molecular Genetics Advance Access first published online on June 21, 2010
This version [Corrected Proof] published online on July 6, 2010
Human Molecular Genetics, doi:10.1093/hmg/ddq251

© The Author 2010. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left–right patterning defects
Jamie Bentham1,2,, Anna C. Michell1,2,, Helen Lockstone2, Daniel Andrew1,2, Jürgen E. Schneider1,2, Nigel A. Brown3 and Shoumo Bhattacharya1,2,*
1 Department of Cardiovascular Medicine and 2 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK and 3 St George's, University of London, London SW17 0RE, UK

* To whom correspondence should be addressed. Tel: +44 1865287771; Email: sbhattac@well.ox.ac.uk

Received April 30, 2010; Accepted June 15, 2010

Deficiency of the transcription factor Cited2 in mice results in cardiac malformation, adrenal agenesis, neural tube, placental defects and partially penetrant cardiopulmonary laterality defects resulting from an abnormal Nodal->Pitx2c pathway. Here we show that a maternal high-fat diet more than doubles the penetrance of laterality defects and, surprisingly, induces palatal clefting in Cited2-deficient embryos. Both maternal diet and Cited2 deletion reduce embryo weight and kidney and thymus volume. Expression profiling identified 40 embryonic transcripts including Pitx2 that were significantly affected by embryonic genotype-maternal diet interaction. We show that a high-fat diet reduces Pitx2c levels >2-fold in Cited2-deficient embryos. Taken together, these results define a novel interaction between maternal high-fat diet and embryonic Cited2 deficiency that affects Pitx2c expression and results in abnormal laterality. They suggest that appropriate modifications of maternal diet may prevent such defects in humans.



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These authors contributed equally to this work.

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Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left-right patterning defects -- Bentham et al., 10.1093/hmg/ddq251 -- Human Molecular Genetics

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