Multi-disciplinary studies of chick embryos that neural crest ablation have shown that myocardial function is altered prior to the time that neural crest cells would be expected to reach the heart in intact embryos. At the time when myocardial dysfunction can first be seen, the cardiac neural cress cells are in contact with the dorsolateral margin of the pharynx. We have recently found that isolated pharyngeal endoderm can cause similar changes in cultured myocardium. The effect can be blocked by a polyclonal neutralizing antibody to FGF. These observations have led to the hypothesis that 1) an interaction of neural crest cells with endoderm is required for suppression of an FGF-like signal that leads to abnormal myocardial development in neural crest cells to suppress the endodermally-derived signal. The hypotheses will be tested first by localizing expression of FGF ligands and receptors in neural crest, endoderm, and myocardium and then in tissue recombinations of neural crest and/or endoderm with myocardium in vitro. Various techniques will be used to interfere with FGF signaling in the tissue recombinations and in explant cultures. Various techniques will be used to interfere with FGF signaling in the tissue recombinations and in explant cultures. Neural crest ablations and back-transplantations will be used to modify expression of FGF modulating factors and to interfere with FGF signaling in intact embryos. Finally, we will apply excess retinoic acid to neural crest cells to alter the ability of neural crest to modulate the FGF signaling mechanism. The experiments proposed will elucidate a previously unrecognized function of cardiac neural crest cells and characterize the interactions of neural crest cells with pharyngeal endoderm. These interactions appear to be critical for normal myocardial development and in their absence, myocardial developmental history is altered. We believe that this may lead to the high mortality in children with neural crest-related heart defects even after surgical repair.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
7P01HL036059-15
Application #
6500484
Study Section
Project Start
2001-04-01
Project End
2002-03-31
Budget Start
Budget End
Support Year
15
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Type
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Palatinus, Joseph A; O'Quinn, Michael P; Barker, Ralph J et al. (2011) ZO-1 determines adherens and gap junction localization at intercalated disks. Am J Physiol Heart Circ Physiol 300:H583-94
Evans, Sylvia M; Yelon, Deborah; Conlon, Frank L et al. (2010) Myocardial lineage development. Circ Res 107:1428-44
Kirby, Margaret L; Hutson, Mary R (2010) Factors controlling cardiac neural crest cell migration. Cell Adh Migr 4:609-21
Hutson, Mary Redmond; Zeng, Xiaopei Lily; Kim, Andrew J et al. (2010) Arterial pole progenitors interpret opposing FGF/BMP signals to proliferate or differentiate. Development 137:3001-11
Hutson, Mary Redmond; Sackey, Faustina N; Lunney, Katherine et al. (2009) Blocking hedgehog signaling after ablation of the dorsal neural tube allows regeneration of the cardiac neural crest and rescue of outflow tract septation. Dev Biol 335:367-73
Gurjarpadhye, Abhijit; Hewett, Kenneth W; Justus, Charles et al. (2007) Cardiac neural crest ablation inhibits compaction and electrical function of conduction system bundles. Am J Physiol Heart Circ Physiol 292:H1291-300
Graham, Victoria; Zhang, Hengtao; Willis, Shannon et al. (2006) Expression of a two-pore domain K+ channel (TASK-1) in developing avian and mouse ventricular conduction systems. Dev Dyn 235:143-51
Hutson, Mary R; Zhang, Ping; Stadt, Harriett A et al. (2006) Cardiac arterial pole alignment is sensitive to FGF8 signaling in the pharynx. Dev Biol 295:486-97
Lindsey, Merry L; Escobar, G Patricia; Mukherjee, Rupak et al. (2006) Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. Circulation 113:2919-28
Gourdie, Robert G; Ghatnekar, Gautam S; O'Quinn, Michael et al. (2006) The unstoppable connexin43 carboxyl-terminus: new roles in gap junction organization and wound healing. Ann N Y Acad Sci 1080:49-62

Showing the most recent 10 out of 116 publications