Proper coordination of neural crest migration is an absolute requirement for normal cardiovascular development - most particularly outflow tract morphogenesis. The gap junction protein Cx43 has a key function in this directed migration of cardiac neural crest cells. The molecular mechanism by which Cx43 affects neural crest motility is unknown. The forces driving cell migration are generated largely by the dynamics of the actin cytoskeleton. We hypothesize that proteins mediating linkage between connexins and actin are candidates for regulators of cell motility. One molecule known to mediate interaction between connexins and actin is ZO1 - a PDZ protein related to the Drosophila tumor suppressor protein discs large. The Gourdie lab has shown that Cx43-ZO1 interaction is critical to developmental remodeling of the extent of gap junctional contact between myocardial cells. Furthermore, we have data showing that inhibition of ZO1- Cx43 interaction decreases neural crest outgrowth in vitro and reduces motility of fibroblasts and epithelial cells in cultured monolayers in a """"""""scratch wound"""""""" migration assay. We will test the hypothesis that ZO1-Cx43 interaction is an integral part of a mechanism involved in regulation of cell-cell contact pattern and migration of neural crest cells by determining: 1. Whether factors known to stimulate neural crest cell motility, affect interactions between Cx43, ZO-1 and other connexin interacting proteins in vitro; 2. Whether inhibition of ZO1-Cx43 interaction is sufficient to disrupt regulation of the rate and directionality of neural crest cell migration in vitro; and 3. if ZO1-Cx43 interaction is necessary for the directed migration of neural crest cells in vivo. This study will provide new insight into molecular regulation of neural crest migration in the embryo and origins of birth defects in humans. ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
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Schramm, Charlene A
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Medical University of South Carolina
Anatomy/Cell Biology
Schools of Medicine
United States
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Palatinus, Joseph A; Gourdie, Robert G (2016) Diabetes Increases Cryoinjury Size with Associated Effects on Cx43 Gap Junction Function and Phosphorylation in the Mouse Heart. J Diabetes Res 2016:8789617
Gourdie, Robert G; Myers, Tereance A; McFadden, Alex et al. (2012) Self-organizing tissue-engineered constructs in collagen hydrogels. Microsc Microanal 18:99-106
Palatinus, Joseph A; Rhett, J Matthew; Gourdie, Robert G (2012) The connexin43 carboxyl terminus and cardiac gap junction organization. Biochim Biophys Acta 1818:1831-43
Rhett, Joshua Matthew; Gourdie, Robert G (2012) The perinexus: a new feature of Cx43 gap junction organization. Heart Rhythm 9:619-23
O'Quinn, Michael P; Palatinus, Joseph A; Harris, Brett S et al. (2011) A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury. Circ Res 108:704-15
Palatinus, Joseph A; Rhett, Joshua M; Gourdie, Robert G (2011) Enhanced PKC? mediated phosphorylation of connexin43 at serine 368 by a carboxyl-terminal mimetic peptide is dependent on injury. Channels (Austin) 5:236-40
Rhett, J Matthew; Jourdan, Jane; Gourdie, Robert G (2011) Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol Biol Cell 22:1516-28
Palatinus, Joseph A; Rhett, J Matthew; Gourdie, Robert G (2010) Translational lessons from scarless healing of cutaneous wounds and regenerative repair of the myocardium. J Mol Cell Cardiol 48:550-7
Ghatnekar, Gautam S; O'Quinn, Michael P; Jourdan, L Jane et al. (2009) Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding. Regen Med 4:205-23
Sedmera, David; Harris, Brett S; Grant, Elizabeth et al. (2008) Cardiac expression patterns of endothelin-converting enzyme (ECE): implications for conduction system development. Dev Dyn 237:1746-53

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