Understanding the causes of congenital heart defects will first require an understanding of embryonic heart development. The long range objective of this research is to describe the molecular and cellular events leading to differentiation and growth of the vertebrate heart. The goal of the proposed research is to examine the role of tinman-related homeodomain proteins, XNkx-2.5 and Xtin1 in vertebrate heart development. Both of these Xenopus genes are related to Drosophila tinman, which is essential for heart development in flies. XNkx-2.5 and Xtin1 are expressed in the cardiogenic region of the embryo from the very earliest stages of heart development and expression continues in the adult myocardium. Knockout of the mouse homolog of XNkx-2.5 results in embryonic death due to defects in heart folding and morphogenesis. Very recently it has been demonstrated that over-expression of XNkx-2.5 or Xtin1 during Xenopus embryogenesis results in a dramatic increase in the size of the heart. Overall, the expression patterns, the mouse knockout results and the over-expression studies strongly imply an essential role for tinman-related sequences in cardiac development. Research in this proposal focuses on two specific objectives. 2) Identification of the protein domains within the vertebrate tinman-related sequences that are required for biological activity. 2) Identification of the downstream target genes of XNkx-2.5 and Xtin1 in the heart development pathway. Taken together, this information seeks to increase the understanding of the mode of action of cardiogenic homeodomain proteins. These experiments exploit the unique advantages of the Xenopus embryo system to study the mechanisms underlying vertebrate cardiac development, and this knowledge will hopefully contribute to an understanding of the causes of congenital heart defects in humans and potentially lead to methods for prevention and treatment.
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