Fueling left-right asymmetry: the role of glycolysis in stomach curvature

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Project Summary Left-right (LR) differences in size, shape and/or anatomical position exist in almost every organ system. Consequently, abnormal LR asymmetry (known as heterotaxy, HTX) often leads to multiple, life threatening birth defects involving complex malformations and discordant laterality between organs. While the early embryonic events that establish global LR asymmetry have been well studied, it is the later-stage, organ- specific LR asymmetric morphogenesis events that are critical for normal anatomy; yet, for most organs, the molecular and cellular processes that sculpt their individual LR asymmetries have not been elucidated. This application will explore the novel and surprising concept that LR asymmetries in GLYCOLYSIS—the primordial metabolic pathway that breaks down glucose to generate ATP—are integrally involved in asymmetric organ morphogenesis. Published work has shown that leftward curvature of the stomach, an archetypical LR asymmetry conserved among vertebrates, depends on LR asymmetric rearrangements of mesenchymal cells into an epithelium (mesenchymal-to-epithelial transition; MET), causing thinning and expansion of the left stomach wall. Recent left vs right transcriptome profiling subsequently revealed that glycolysis enzymes are upregulated in the left side of the stomach during curvature. As glycolysis (as opposed to mitochondrial respiration) is known to promote epithelial-mesenchymal plasticity in other contexts, this unexpected finding raises the intriguing possibility that LR asymmetric glycolysis may facilitate the LR asymmetric MET that drives curvature morphogenesis. In the proposed project, this idea will be rigorously tested by exploiting the unique attributes of two different amphibian embryos, executing metabolomics, mass spectrometry imaging, glycolytic flux analyses, pharmacological perturbations, and left- vs right-targeted tests of gene function, to determine the function of glycolysis genes (Aim 1), and glycolytic metabolism (Aim 2) in stomach curvature morphogenesis. Successful completion of this R21 will therefore substantiate the intriguing premise that organ laterality is shaped by LR asymmetries in glycolysis, such that aberrant metabolic states may contribute to the development of laterality-related birth defects.