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Modulation of eomes activity alters the size of the developing heart: implications for in utero cardiac gene therapy
Kenneth Ryan1, Andreas P Russ, Robert J Levy
1Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Joseph Stokes Jr. Research Institute, Division of Cardiology, Abramson Research Center, Philadelphia, PA 19104-4318, USA. ryank@email.chop.edu
Insights
Researchers explored the role of Eomesodermin (Eomes) in heart development. Manipulating Eomes activity in Xenopus embryos influenced ventricular size, suggesting potential gene therapy targets for congenital heart defects.
Area of Science:
- Developmental Biology
- Genetics
- Cardiovascular Research
Background:
- Congenital heart disease (CHD) is a leading cause of infant mortality, often linked to genetic abnormalities.
- Gene therapy strategies for CHD remain largely unexplored.
- The role of Eomesodermin (Eomes), a T-box transcription factor, in cardiac development is not well understood.
Purpose of the Study:
- To investigate the function of Eomesodermin (Eomes) during cardiac development.
- To determine if Eomes activity influences ventricular formation and growth.
Main Methods:
- Studied Eomes expression in the developing Xenopus heart, particularly in the ventricle.
- Utilized conditional dominant-interfering (GR-Eomes--engrailed) and activating (GR-Eomes-VP16) approaches to manipulate Eomes activity.
- Observed the effects of Eomes manipulation on ventricular development and myocardial size.
Main Results:
- Eomes is expressed in the developing Xenopus heart, with significant myocardial distribution in the ventricle.
- Suppression of Eomes activity (GR-Eomes-enR) led to suppressed ventricular development.
- Activation of Eomes activity (GR-Eomes-VP16) resulted in increased ventricular myocardial size.
Conclusions:
- Eomesodermin plays a critical role in regulating ventricular size during late cardiac development.
- These findings suggest a potential gene therapy target for conditions like hypoplastic left heart syndrome and hypertrophic cardiomyopathy.
Abstract:
Congenital heart disease is the most prevalent cause of infant morbidity and mortality in developed countries. The mechanisms responsible for many specific types of congenital cardiac malformations are strongly associated with gene abnormalities. However, at this time no strategies for gene therapy of the various congenital heart malformations have been investigated. In the present studies we focus on Eomesodermin (Eomes), a T-box transcription factor expressed in developing vertebrate mesoderm. Although Eomes is required for early mesodermal patterning and differentiation, the role of Eomes in cardiac development is unknown. In the present studies we demonstrate that Eomes is expressed in the developing heart, with a pronounced myocardial distribution in the Xenopus ventricle during late cardiac development. Using either a conditional dominant-interfering approach (GR-Eomes--engrailed) or an Eomes-activating approach (GR-Eomes-VP16) we demonstrate that manipulating Eomes activity during late cardiac development can either suppress ventricular development (GR-Eomes-enR) or increase ventricular myocardial size (GR-Eomes-VP16). Thus, a potential gene therapy approach for treating both congenital ventricular hypoplasia (e.g., the hypoplastic left heart syndrome) and hypertrophic cardiomyopathy is hypothetically implicit from the present results.
