The formation of a normal heart requires the tightly regulated activation of a series of genes. This regulation begins early in development as cells progressively lose pluripotency and settle into lineages that result in muscle, endothelium, valves and the connective tissue of the heart. Defining the appropriate lineages is important, but equally important is the modeling of these different cell types into the chambers, valves, septae and conduction system that form a working heart. Among the regulators of the cardiac developmental program are transcription factors from NK-2 family of proteins. First identified in fruit fly as the gene called tinman (because the null mutation gave rise to flies that failed to form a dorsal vessel (the fly's heart)) we now refer to the homologue in man and other chordates as Nkx2-5. Humans with mutations in even one of their copies of Nkx2-5 develop congenital heart defects. Among their problems are malformed septae that separate the chambers of the heart, heart valve defects and abnormal regulation of heart contraction. Recently, mutations in a related protein Nkx2-6, was shown to cause problems in the outflow tract of the heart, the region that connects the blood pumped by the heart back into the vascular system. The NK-2 genes involved in heart formation have been studied to good advantage in a variety of system, including mouse, chicken, fly, fish and the frog Xenopus laevis. The regulatory division of labor in frog falls to three members of this family, Nkx2-5, Nkx2-3 and Nkx2-10 (the likely homologue of human Nkx2-6). We propose experiments to track the role of each of these transcription factors during early cardiac development, define the protein domains of each that confer unique function and identify how the expression of each is regulated. This will allow us to separate the regulatory pathways that must be coordinated to form a working heart.

Public Health Relevance

Congenital heart defects in human affect 1% of all newborns, and present a persistent health challenge for the rest of their lives. One of the genetic causes of congenital heart defects are mutations in the transcription factors Nkx2-5, and Nkx2-6 that leads to the misregulation of genes needed for correct heart formation. These studies aim at identifying the genes and developmental processes that depend upon these transcription factors to better understand how misregulation can be mitigated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069944-07
Application #
8269765
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
2004-01-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
7
Fiscal Year
2012
Total Cost
$317,948
Indirect Cost
$105,098
Name
University of Iowa
Department
Biochemistry
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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