# Left-right patterning abnormalities and cardiac morphogenesis

> **NIH NIH P01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $442,471

## Abstract

ABSTRACT
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 w...

## Key facts

- **NIH application ID:** 10111565
- **Project number:** 5P01HL134599-05
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Stephanie M Ware
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $442,471
- **Award type:** 5
- **Project period:** 2017-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111565

## Citation

> US National Institutes of Health, RePORTER application 10111565, Left-right patterning abnormalities and cardiac morphogenesis (5P01HL134599-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10111565. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*