Cadherins play critical roles during embryonic development. Extracellularly, they mediate specific cell-cell adhesion, while intracellularly they interact with the catenins and through them with actin cytoskeleton. There is growing evidence that signal transduction via cadherins and catenins induces a variety of cellular responses. In cardiac muscle, N-cadherin has been shown to be important for maintaining structure and function, including myofibril organization and myocyte contraction. The goal of this project is to establish a role for N- cadherin in early events of cardiac muscle formation. Our initial results indicate that N-cadherin is required for maintaining the adhesion between cardiac myocytes of the early mouse embryo. We propose that N-cadherin- mediated cell adhesion regulates intercellular communication and myofibril formation in the early myocardium. We will analyze the ability of cardiac myocytes from N-cadherin-deficient transgenic mouse embryos to assemble gap junctions and desmosomes. The expression and cellular localization of contractile proteins will also be examined in N-cadherin-minus cardiac myocytes. N-cadherin double knockout (DKO) embryonic stem (ES) cell lines will be established. After transfection with GATA-4, the N-cadherin-null ES cells will be differentiated into cardiac muscle in vitro. The ability of epithelial (E-) cadherin to rescue the N-cadherin-deficient cardiomyocytes will be determined. The DKO ES cell line will be transfected with mutant N-cadherins to determine which domains are required for its proper function in cardiac myocytes. Mutant N-cadherins include functionally altered, chimeric, and truncated molecules. Lastly, we will determine if upregulation of N-cadherin is compatible with normal cardiac development. The proposed research will elucidate N-cadherin's role in myocardium formation. In broader terms our results will contribute to our understanding of how cadherins regulate cell morphology and behavior. They also will shed light on the specificity of cadherin function in a particular tissue, in this case cardiac muscle.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL057554-01A1
Application #
2399126
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1997-08-01
Project End
2002-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bhattacharya, Jahar; Matthay, Michael A (2013) Regulation and repair of the alveolar-capillary barrier in acute lung injury. Annu Rev Physiol 75:593-615
Kostetskii, Igor; Li, Jifen; Xiong, Yanming et al. (2005) Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ Res 96:346-54
Luo, Yang; Kostetskii, Igor; Radice, Glenn L (2005) N-cadherin is not essential for limb mesenchymal chondrogenesis. Dev Dyn 232:336-44
Luo, Yang; Radice, Glenn L (2003) Cadherin-mediated adhesion is essential for myofibril continuity across the plasma membrane but not for assembly of the contractile apparatus. J Cell Sci 116:1471-9
Luo, Yang; Lee, Anee; Shen, Hao et al. (2003) Altering tissue tropism of Listeria monocytogenes by ectopically expressing human E-cadherin in transgenic mice. Microb Pathog 35:57-62
Ferreira-Cornwell, M Celeste; Luo, Yang; Narula, Navneet et al. (2002) Remodeling the intercalated disc leads to cardiomyopathy in mice misexpressing cadherins in the heart. J Cell Sci 115:1623-34
Xu, X; Li, W E; Huang, G Y et al. (2001) Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions. J Cell Biol 154:217-30
Kostetskii, I; Moore, R; Kemler, R et al. (2001) Differential adhesion leads to segregation and exclusion of N-cadherin-deficient cells in chimeric embryos. Dev Biol 234:72-9
Esni, F; Johansson, B R; Radice, G L et al. (2001) Dorsal pancreas agenesis in N-cadherin- deficient mice. Dev Biol 238:202-12
Luo, Y; Ferreira-Cornwell, M; Baldwin, H et al. (2001) Rescuing the N-cadherin knockout by cardiac-specific expression of N- or E-cadherin. Development 128:459-69

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