Cited2is required both for heart morphogenesis and establishment of the left-right axis in mouse development

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 Cited2in 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.

Development of the venous pole of the heart in the frog Xenopus laevis: A morphological study with special focus on the development of the venoatrial connections

“…This is surprising since it is a well-known fact that human congenital cardiac malformations with bilaterally symmetric arrangement of the atrial appendages, so-called left and right atrial isomerism, are frequently associated with abnormal connections of the systemic and pulmonary venous tributaries (Uemura et al, 1996;Smith et al, 2006). During the past few years, genetic mouse models for left as well as right atrial isomerism have been used to analyze the role of L-R axis specification in the development of the venous heart pole (Liu et al, 2002;Anderson et al, 2004;Weninger et al, 2005;Hildreth et al, 2009). Analyses of Pitx2c-deficient mice, for example, have shown that this transcription factor, which normally is expressed only in the left half of the heart tube (Franco et al, 2000;Campione et al, 2001), suppresses a default program of sinus node formation in the left atrium (Mommersteeg et al, 2007).…”

Developmental regulation of hypoxia-inducible factor 1 and prolyl-hydroxylases in pulmonary vascular smooth muscle cells

“…Similar to PHD2 and FIH, CITED2 activation by hypoxia might indicate a role for this molecule in the rapid inactivation of the hypoxic response upon reoxygenation. CITED2 may play a role in heart morphogenesis and the establishment of left-right asymmetry in the early embryo (20)(21)(22).…”

Cited2, a Transcriptional Modulator Protein, Regulates Metabolism in Murine Embryonic Stem Cells

“…2 -binding protein (CBP)/p300 interacting transactivator with glutamic acid (Glu) and aspartic acid (Asp)-tail 2 (Cited2) is a multifunctional protein essential for mouse embryogenesis (1)(2)(3)(4). Embryos with a deletion of Cited2 have defects in multiple organs including the heart, liver, and adrenal glands and do not survive beyond E14.5 (1)(2)(3)(4).…”

“…Embryos with a deletion of Cited2 have defects in multiple organs including the heart, liver, and adrenal glands and do not survive beyond E14.5 (1)(2)(3)(4). A knock-out of Cited2 in mice causes defects in arterial and ventricular septum and outflow tract, which are responsible for embryonic lethality of a Cited2 gene deletion (1,3,4). By interacting with hepatocyte nuclear factor 4␣, Cited2 regulates lipid and carbohydrate metabolism in embryos (2).…”