Iroquois Homeobox Transcription Factors in Heart Development and Physiology

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DESCRIPTION (provided by applicant): Transcription factors are key regulators of several aspects of organogenesis, and in the heart, several important DNA-binding transcription factors are powerful regulators of cardiac cell fate and organogenesis. Less well studied are the roles played by transcription factors in patterning of physiological functions, such as the functional specialization of the conduction system. These functions are intimately linked to the developmental regulation of the heart and are likely to be at the root of several human congenital heart diseases that affect cardiac physiology, such as cardiomyopathies and arrhythmias. The Irx family of transcription factors is emerging as a key class of regulators that are crucial for the transcriptional regulation of cardiac physiological processes. Six members of the family, Irx1-Irx6, are expressed in distinct but overlapping patterns in the developing mammalian heart. Preliminary results indicate that Irx genes are important in very specific aspects of cardiac development, and that genetic redundancy between Irx genes masks their true roles in the developing heart. We hypothesize that the Iroquois homeobox (Irx) family of transcription factors are key patterning and differentiation factors that confer cell type-specific properties to specialized cardiac lineages, and thereby are involved in establishing important aspects of late fetal heart development and postnatal physiology. To test our hypothesis, we will examine the specific and overlapping functions of Irx factors in regulating key aspects of cell type specialization in the developing heart. We propose three Specific Aims: 1. To define the role of Irx3 in establishing the identity of the developing distal conduction system of the mouse heart. 2. To elucidate the overlapping roles played by Irx3 and Irx5 in establishing transcriptional programs in cardiac development and in postnatal heart function. 3. To understand the molecular specialization of Irx protein function. The information generated by the results of each aim will be crucial to our understanding of heart patterning and the mechanism by which late patterning events affect postnatal physiology. These findings will be applicable to the study of the cardiac conduction system, cardiac growth, and intercellular communication during organogenesis. The results obtained will also be relevant to human diseases that affect these processes, including arrhythmias after infarct and cardiac remodeling in heart failure. PUBLIC HEALTH RELEVANCE: Transcription factors are proteins that turn other genes on or off, and in the heart, several important transcription factors are essential for the normal formation of the heart. Less well studied are the roles played by transcription factors in making sure the heart functions properly after it has formed. These functions are likely to be at the root of several human heart diseases that affect cardiac function, such as cardiomyopathies and arrhythmias. We will study the Irx family of transcription factors in the mouse heart, as we believe that they are key to establishing important aspects heart physiology. The results obtained will be relevant to human diseases that affect these processes, including arrhythmias after infarct and cardiac remodeling in heart failure.