Metabolism and Malrotation

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Project Summary/Abstract Intestinal malrotation (IM) is a highly prevalent birth defect that can lead to life-threatening conditions necessitating surgical intervention and long-term supplemental nutrition. Atrazine (ATR), a ubiquitous herbicide that perturbs electron transport chain (ETC) reactions, was found to cause IM at high frequency. Preliminary data show that ATR decreases mitochondrial respiration (i.e., oxidative phosphorylation; oxphos) and increases glycolytic activity in the developing intestine. However, while early gut development can subsist on glycolysis alone, later gut development requires oxphos; thus, ATR may block a critical metabolic switch from glycolysis to mitochondrial respiration (oxphos) during intestine morphogenesis. During normal gut development, intestinal rotation occurs simultaneously with gut lengthening, and shorter gut lengths are often associated with IM, suggesting that gut elongation mechanisms are integral to the rotation process. Indeed, cellular analyses reveal that ATR perturbs crucial events required to drive intestinal lengthening, including early mesenchymal-to-epithelial transitions (MET) and, later, interkinetic nuclear migration (IKNM) -- common morphogenetic processes recently found to be influenced by cellular metabolic states. Together, these data suggest that a metabolic switch from glycolysis to oxphos drives proper intestine rotation by regulating the timing and/or localization of MET and IKNM events during gut elongation. This hypothesis will be tested using innovative metabolomics technologies to determine: 1) how ATR affects the spatiotemporal dynamics of cellular metabolism during intestine morphogenesis, and 2) how dynamic cellular metabolic states affect the timing and localization of MET and IKNM within the developing intestine. Successful completion of these aims will illuminate the poorly understood etiology of IM, and will have implications for the role of metabolism-altering toxins, diseases, and/or pregnancy conditions in the development of structural birth defects that depend on MET- and/or IKNM-mediated morphogenesis.