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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052746-02
Application #
2445281
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1996-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
Newman, C S; Reecy, J; Grow, M W et al. (2000) Transient cardiac expression of the tinman-family homeobox gene, XNkx2-10. Mech Dev 91:369-73
Patterson, K D; Drysdale, T A; Krieg, P A (2000) Embryonic origins of spleen asymmetry. Development 127:167-75
Cleaver, O; Seufert, D W; Krieg, P A (2000) Endoderm patterning by the notochord: development of the hypochord in Xenopus. Development 127:869-79
Patterson, K D; Cleaver, O; Gerber, W V et al. (2000) Distinct expression patterns for two Xenopus Bar homeobox genes. Dev Genes Evol 210:140-4
Patterson, K D; Krieg, P A (1999) Hox11-family genes XHox11 and XHox11L2 in xenopus: XHox11L2 expression is restricted to a subset of the primary sensory neurons. Dev Dyn 214:34-43
Gerber, W V; Yatskievych, T A; Antin, P B et al. (1999) The RNA-binding protein gene, hermes, is expressed at high levels in the developing heart. Mech Dev 80:77-86
Newman, C S; Krieg, P A (1999) Alternative splicing and embryonic expression of the Xenopus mad4 bHLH gene. Dev Dyn 215:170-8
Newman, C S; Krieg, P A (1999) The Xenopus bagpipe-related homeobox gene zampogna is expressed in the pharyngeal endoderm and the visceral musculature of the midgut. Dev Genes Evol 209:132-4
Grow, M W; Krieg, P A (1998) Tinman function is essential for vertebrate heart development: elimination of cardiac differentiation by dominant inhibitory mutants of the tinman-related genes, XNkx2-3 and XNkx2-5. Dev Biol 204:187-96
Newman, C S; Krieg, P A (1998) tinman-related genes expressed during heart development in Xenopus. Dev Genet 22:230-8

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