Symmetry breakage in the amphibian embryo

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Breakage of bilateral symmetry in vertebrates remains controversial: while a cilia-driven leftward flow is required in fish and mammals at gastrula/neurula stages, amphibian embryos show functionally relevant asymmetries already at cleavage. The ion flux model in frog postulates asymmetric segregation of low-molecular weight determinant(s) such as serotonin via an ion pump driven electrophoresis-like process through gap junctions. We recently showed that leftward flow is conserved in amphibians, and that inhibition of flow caused left-right (LR) defects. The main aims of this research proposal are (1) to determine if and how early asymmetries are connected to leftward flow at later stages; (2) to investigate whether or not early asymmetric determinants identified in frog act in mammalian left-right axis formation. Preliminary data suggest that these early determinants might be required for the development of a functional leftward flow in amphibian and mammalian embryos. Descriptive examinations will be performed to localize determinants during relevant embryonic stages. Functional experiments in frog, mouse and rabbit embryos will investigate H*-K*-ATPase, V-ATPase and serotonin in gain- and loss-of-function scenarios to unravel their roles with respect to flow characteristics (velocity and directionality) and laterality (marker genes and organ situs). The long-term goal of this study therefore is to develop a unifying model of vertebrate laterality determination.