Congenital heart defects (CHDs) are a significant cause of morbidity and mortality, affecting over 1.5 million children and adults in the United States. Heterotaxy syndrome is a multisystem disorder characterized by a spectrum of CHDs that are attributable, at least in part, to abnormal left-right asymmetry. Although the link between left-right patterning and subsequent cardiac morphogenesis is not well understood, it is apparent that the ventricular chamber morphogenic defects seen in heterotaxy are more diverse than what would be expected from simple disruption of the left-right axis. This research will investigate the cellular and molecular mechanisms underlying abnormal cardiac morphogenesis observed in heterotaxy using two mouse models of left-right patterning defects: Foxj1 and Zic3 deficient mice. Foxj1 is required for ciliogenesis and mice deficient for this gene fail to develop cilia at the node, a tissue required for normal left-right patterning. Zic3, the gene responsible for X-linked heterotaxy, exhibits abnormalities of the primitive streak including the node. Previously, we demonstrated that expression of Zic3 is required by the mesendodermal cells of the primitive streak for normal cardiac development, but is not required in the heart. The posterior primitive streak gives rise to cardiac progenitor/precardiac mesoderm (CPPM), and the anterior primitive streak gives rise to the ciliated node, thus Zic3 deficiency may cause CHDs via temporally distinct, combinatorial events. These results could provide explanations for the wide phenotypic variability identified in heterotaxy, suggesting a ?multiple developmental hits? model. Our findings suggest the novel hypothesis that the diverse spectrum of CHDs observed in heterotaxy results from abnormal specification, proliferation, and/or cell fate of cardiac progenitors that is distinct from the later left-right patterning effects on heart looping. We will test this hypothesis in both mouse models.
The aims of this study are to: 1) determine whether CPPM and node cells independently cause CHDs, and whether cell polarity abnormalities underlie early and/or late stage events; and 2) test the hypothesis that distinct cardiac-lineages are impacted in CHDs from mice with different genetic causes of left- right patterning abnormalities. The overarching hypothesis is that PCCM abnormalities and left-right abnormalities have distinct contributions to the CHDs identified in heterotaxy and that abnormalities in cell proliferation or cell polarity underlie these abnormalities. By delineation of Zic3 function in early mesoderm, we will acquire essential information about normal primitive streak and node formation, left-right axis specification, and their relationship to cardiac looping and ventricular morphogenesis. Identification of the cell lineage contribution to CHDs seen in heterotaxy will provide novel information about causation and phenotypic heterogeneity. Collectively, these studies will define the requirement of gastrulation-stage and node-stage molecular interactions along with their impact on cell fate specification necessary for normal cardiac morphogenesis.

Public Health Relevance

Congenital heart defects are the most common birth defect, have high morbidity and mortality, and their economic impact is tremendous. Our studies using animal models of human disease will identify the mechanisms by which a group of heart defects develop; these results will increase our understanding of why heart defects occur and are so variable. This understanding is important for prevention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL134599-02
Application #
9430449
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Schramm, Charlene A
Project Start
Project End
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Vincentz, Joshua W; Toolan, Kevin P; Zhang, Wenjun et al. (2017) Hand factor ablation causes defective left ventricular chamber development and compromised adult cardiac function. PLoS Genet 13:e1006922