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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.

Original publication




Journal article


Nat Genet

Publication Date





1189 - 1196


Animals, Body Patterning, Crosses, Genetic, DNA-Binding Proteins, Gene Expression, Heart, Heart Defects, Congenital, Homeodomain Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Nodal Protein, Nuclear Proteins, Organogenesis, Repressor Proteins, Trans-Activators, Transcription Factor AP-2, Transcription Factors, Transforming Growth Factor beta