Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development

Weninger, Wolfgang J., Floro, Kylie Lopes, Bennett, Michael B., Withington, Sarah L., Preis, Jost I., Barbera, Juan Pedro Martinez, Mohun, Timothy J. and Dunwoodie, Sally L. (2005) Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development. Development, 132 6: 1337-1348. doi:10.1242/dev.01696

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Author Weninger, Wolfgang J.
Floro, Kylie Lopes
Bennett, Michael B.
Withington, Sarah L.
Preis, Jost I.
Barbera, Juan Pedro Martinez
Mohun, Timothy J.
Dunwoodie, Sally L.
Title Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development
Formatted title
Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development
Journal name Development   Check publisher's open access policy
ISSN 0950-1991
Publication date 2005-03
Sub-type Article (original research)
DOI 10.1242/dev.01696
Open Access Status File (Publisher version)
Volume 132
Issue 6
Start page 1337
End page 1348
Total pages 12
Place of publication Cambridge, England
Publisher Company of Biologists
Language eng
Subject 11 Medical and Health Sciences
06 Biological Sciences
Abstract Establishment of the left-right axis is a fundamental process of vertebrate embryogenesis. Failure to develop left-right asymmetry leads to incorrect positioning and morphogenesis of numerous internal organs, and is proposed to underlie the etiology of several common cardiac malformations. The transcriptional modulator Cited2 is essential for embryonic development: Cited2-null embryos die during gestation with profound developmental abnormalities, including cardiac malformations, exencephaly and adrenal agenesis. Cited2 is also required for normal establishment of the left-right axis; we demonstrate that abnormal heart looping and right atrial and pulmonary isomerism are consistent features of the left-right-patterning defect. We show by gene expression analysis that Cited2 acts upstream of Nodal, Lefty2 and Pitx2 in the lateral mesoderm, and of Lefty1 in the presumptive floor plate. Although abnormal left-right patterning has a major impact on the cardiac phenotype in Cited2-null embryos, laterality defects are only observed in a proportion of these embryos. We have therefore used a combination of high-resolution imaging and three-dimensional (3D) modeling to systematically document the full spectrum of Cited2-associated cardiac defects. Previous studies have focused on the role of Cited2 in cardiac neural crest cell development, as Cited2 can bind the transcription factor Tfap2, and thus affect the expression of Erbb3 in neural crest cells. However, we have identified Cited2-associated cardiac defects that cannot be explained by laterality or neural crest abnormalities. In particular, muscular ventricular septal defects and reduced cell density in the atrioventricular (AV) endocardial cushions are evident in Cited2-null embryos. As we found that Cited2 expression tightly correlated with these sites, we believe that Cited2 plays a direct role in development of the AV canal and cardiac septa. We therefore propose that, in addition to the previously described reduction of cardiac neural crest cells, two other distinct mechanisms contribute to the spectrum of complex cardiac defects in Cited2-null mice; disruption of normal left-right patterning and direct loss of Cited2 expression in cardiac tissues.
Keyword Developmental Biology
Left-right Axis
Heart Development
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
ERA 2012 Admin Only
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 65 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 13 Aug 2007, 15:08:37 EST