The consistent left-right (LR) asymmetry of the vertebrate bodyplan is a fascinating puzzle of developmental and evolutionary biology, and has profound implications for biomedicine. Laterality defects affect more than 1 in 6000 babies born to term, and the molecular details are crucial to understanding, detection, prevention, and repair of birth defects related to errors of LR patterning. The field is currently in disarray, lacking conceptual models that can link mechanisms uncovered for the LR patterning of mouse and zebrafish embryos to the much earlier mechanisms that have been discovered in Xenopus. Our recent work has identified completely novel ion flow-dependent events that function in early LR patterning and are conserved to frog, chick, and zebrafish. However, the existing models do not explain how voltage gradients can be reliably oriented with respect to the LR axis in chick and mammalian body-plans. Exciting data indicate that endogenous voltage and pH gradients produced by ion channel and pump-dependent current flows in cells and tissues regulate a number of important morphogenetic events in embryonic development and regeneration. The recent explosion of work focused on gene transcription networks and secreted signaling factors have largely neglected these fascinating epigenetic biophysical phenomena. Our lab combines the powerful modern tools of molecular and cell biology, biophysics, physiology, and computer modeling; thus, our work will not only contribute to understanding left-right patterning but also reveal new molecular details of how endogenous ion flows control cell behavior. Our approaches and reagents present a valuable and unique opportunity to resolve the major puzzle of how early, cytoplasmic events that set up asymmetry in large blastomeres aligned with the embryo's midline may function in other animals (such as mammals) where many small cells exist instead. We will resolve this puzzle by addressing the major outstanding questions through (1) determining how 3 specific ion transporters are involved in the imposition of LR asymmetry onto large cell fields by foci of autonomous """"""""organizers"""""""", and (2) characterizing the interaction of polarity and cytoskeleton proteins in controlling the localization and/or behavior of ion fluxes in cells. Together, these experiments take advantage of a powerful set of approaches in a model system (Xenopus) amenable to both molecular genetics and functional biophysics. By capitalizing on the exciting base of preliminary and published data that we have obtained, our work will reveal novel mechanisms that can be used to gain insight into the cell and evolutionary biology of morphogenesis, will integrate this field with mainstream molecular developmental biology, and will ultimately serve as the basis for novel approaches targeting many areas of birth defects, regeneration, and tumor biology. ? ? ?
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