Transcriptional Regulators of Cardiac Gene Expression

University Of Texas Md Anderson Can Ctr, Houston TX

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Abstract

DESCRIPTION (provided by applicant): Congenital malformations of the heart, which occur with a frequency of 8 per 1000 live births, are the most common birth defects observed in children. The frequency of such malformations in miscarriages and stillbirths may be as much as 10-fold greater. An understanding of the genetic bases of these anomalies will require detailed information on the factors controlling heart morphogenesis and gene expression. Several key members of the cardiac regulatory network have been conserved between Drosophila and higher eukaryotes including humans. Concerning transcriptional regulators, the utilization of fly genetics has allowed for a rapid functional analysis of the Tinman, Pannier, U-shaped, D-MEF2. and Seven Up proteins, illuminating their distinct roles in heart formation and myocardial cell specialization. This proposal will further analyze aspects of the regulation, interaction, and function of these essential regulatory factors. While Tinman is a known transcriptional activator of pannier, the probable co-induction of this GATA gene by Decapentaplegic-mediated signaling events remains to be investigated. Both genetic inputs likely culminate in the overlapping expression of Tinman and Pannier in the heart-forming region, and the molecular bases of the functional interaction of these two factors in the regulation of D-mef2 gene transcription will be determined. Additionally, heart induction assays can be used to characterize the conserved cardiogenic domains of Pannier and mouse GATA-4. U-shaped plays a negative role in heart formation and the mechanism of its ability to change Pannier from a transcriptional activator to a repressor must be elucidated. Finally, the regulation of the wingless gene by Seven Up and the role of this secreted growth factor in the functional diversification of cardial cells will be ascertained. Overall, the further elaboration of the functions and interactions of these universal cardiogenic factors, and the cellular processes they control, should provide meaningful insights into fundamental mechanisms controlling heart development and gene expression, in this model organism and more advanced species as well.