Nature Genetics36, 1189 - 1196 (2004)
Published online: 10 October 2004; | doi:10.1038/ng1446
Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway
Simon D Bamforth1, 6, José Bragança1, 6, Cassandra R Farthing1, 6, Jürgen E Schneider1, Carol Broadbent1, Anna C Michell1, Kieran Clarke2, Stefan Neubauer1, Dominic Norris3, Nigel A Brown4, Robert H Anderson5
& Shoumo Bhattacharya1
1
Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
2
Department of Physiology, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
3
MRC Mammalian Genetics Unit, Harwell OX11 0RD, UK.
4
St. George's Hospital Medical School, University of London, Cranmer Terrace, London SW17 0RE, UK.
5
Cardiac Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
Malformations of the septum, outflow tract and aortic arch are the most common congenital cardiovascular defects and occur in mice lacking Cited2, a transcriptional coactivator of TFAP2. Here we show that Cited2-/- mice also develop laterality defects, including right isomerism, abnormal cardiac looping and hyposplenia, which are suppressed on a mixed genetic background. Cited2-/- mice lack expression of the Nodal target genes Pitx2c, Nodal and Ebaf in the left lateral plate mesoderm, where they are required for establishing laterality and cardiovascular development. CITED2 and TFAP2 were detected at the Pitx2c promoter in embryonic hearts, and they activate Pitx2c transcription in transient transfection assays. We propose that an abnormal Nodal-Pitx2c pathway represents a unifying mechanism for the cardiovascular malformations observed in Cited2-/- mice, and that such malformations may be the sole manifestation of a laterality defect.
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