Modulation of eomes activity alters the size of the developing heart: implications for in utero cardiac gene therapy.
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.
Ryan
Kenneth
K
Children'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
Russ
Andreas P
AP
Levy
Robert J
RJ
Wehr
David J
DJ
You
Jingtao
J
Easterday
Mathew C
MC
D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000628:therapy; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D006321:Heart / Q000033:anatomy & histology* / Q000254:growth & development*; D018636:Hypoplastic Left Heart Syndrome / Q000628:therapy; D007814:Larva / Q000033:anatomy & histology / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
C103223:EOMES protein, Xenopus; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D029867:Xenopus Proteins