While much is known about genetically encoded developmental pathways, the mechanisms by which the electrochemical cues interact with traditional morphogenetic pathways during embryogenesis are poorly understood. The central idea of the proposed research is to understand the interplay between major signaling pathway and electrochemical cues during embryogenesis as well as in disease. We have developed technologies to explore the role of electrochemical and other physiologic stimuli during development in the zebrafish. We have demonstrated that Wnt11 non-canonical signaling, a major developmental pathway regulating tissue morphogenesis and organ formation, patterns intercellular electrical coupling in the myocardial epithelium through effects on transmembrane Ca2+ conductance mediated via the L-type Ca2+ channel. The specific aims of the proposed research focus on determining the fundamental molecular mechanisms that lead to the attenuation of L-type Ca2+ channel function by non-canonical Wnt signals, on characterizing how non-canonical Wnt signals compartmentalize and affect different Ca2+ domains in excitable as well as non-excitable tissues and on determining how electrochemical signals modulated by Wnt11 regulate cardiac morphogenesis and cardiac function. The finding that Wnt non-canonical signaling modulates the transmebrane conductance of the L-type Ca2+ channel represents a novel limb of Wnt/Ca2+ signaling. Furthermore, it establishes a role for a major developmental pathway in the integration of intracellular and extracellular ion fluxes, and thus provides a new paradigm for studying the interplay between development and physiology, and for understanding how function and form interact not only during embryogenesis, but also during disease state.
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