Some of the most common congenital heart defects (CHD) in humans are attributable to abnormalities in the cardiac neural crest, a population of ectodermally-derived cells that populates the aortic arch and proximal pulmonary arteries, cardiac outflow tract, and ductus arteriosus, where they form smooth muscle and connective tissue. Ventricular abnormalities, characterized by hypoplastic left or right ventricular chambers, are also commonly seen in newborns. Despite detailed anatomic and physiologic descriptions of these types of CHD, little is known of the molecular mechanisms that control development of the cardiac neural crest or the ventricular chambers. We have discovered two novel basic helix-loop-helix (bHLH) transcription factors, dHAND and eHAND, that are expressed in the cardiac neural crest and developing right and left ventricular chambers, respectively, during embryonic development. The HAND proteins are the earliest chamber-restricted transcription respectively, during embryonic development. The HAND proteins are the earliest chamber-restricted transcription factors identified to date. Inactivation of these genes in mouse or chick embryos result in severe defects in heart development and implicates these factors in chamber specification and neural crest development. The goals of this project are to define the mechanisms that regulate HAND gene expression and to determine the functions of dHAND and eHAND in ventricular and cardiac neural crest development. These studies will be closely interrelated with other projects in this SCOR designed to define the target genes that are transcriptionally regulated by the HAND proteins and the genes that are involved in ventricular and cardiac neural crest defects associated with human CHD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL061033-02
Application #
6302535
Study Section
Project Start
2000-01-28
Project End
2000-12-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$177,402
Indirect Cost
City
Dallas
State
TX
Country
United States
Zip Code
75390
Hullinger, Thomas G; Montgomery, Rusty L; Seto, Anita G et al. (2012) Inhibition of miR-15 protects against cardiac ischemic injury. Circ Res 110:71-81
Song, Kunhua; Nam, Young-Jae; Luo, Xiang et al. (2012) Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485:599-604
O'Rourke, Jason R; Olson, Eric N (2011) Modulating the MicroRNArchitecture of an aging aorta. Circ Res 109:1098-9
Xin, Mei; Kim, Yuri; Sutherland, Lillian B et al. (2011) Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal 4:ra70
Montgomery, Rusty L; Hullinger, Thomas G; Semus, Hillary M et al. (2011) Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124:1537-47
Porrello, Enzo R; Olson, Eric N (2010) Building a new heart from old parts: stem cell turnover in the aging heart. Circ Res 107:1292-4
Kwon, Chulan; Qian, Li; Cheng, Paul et al. (2009) A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate. Nat Cell Biol 11:951-7
Barlow, Gillian M; Micales, Bruce; Chen, Xiao-Ning et al. (2002) Mammalian DSCAMs: roles in the development of the spinal cord, cortex, and cerebellum? Biochem Biophys Res Commun 293:881-91
Barlow, G M; Micales, B; Lyons, G E et al. (2001) Down syndrome cell adhesion molecule is conserved in mouse and highly expressed in the adult mouse brain. Cytogenet Cell Genet 94:155-62
Yamagishi, H; Yamagishi, C; Nakagawa, O et al. (2001) The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation. Dev Biol 239:190-203

Showing the most recent 10 out of 16 publications