Johanson-Blizzard Syndrome (JBS) is an autosomal recessive disorder, characterized by congenital exocrine pancreatic insufficiency, multiple malformations, and severe cognitive impairments. JBS results from mutations in the gene UBR1, an E3 ubiquitin ligase. The molecular and cellular mechanisms that underlie UBR1-mediated disease pathogenesis in JBS patients remain elusive. Here we report that loss-of-function mutations in the C. elegans homolog, UBR-1, lead to behavioral and physiological defects in a small motor circuit, involving the pre-motor interneurons AVE, RIM and AVA that controls body curvature during backward locomotion. In addition, we determined that AVA coordinates backward locomotion by setting up phasic activity lags in A motorneurons. In ubr-1 mutant, activities of these A motorneurons become in-sync, leading to backward locomotion and body curvature defects. We have identified a novel regulatory role for UBR-1 in maintaining synaptic glutamate homeostasis. We provide metabolic as well as neurophysiology evidence that essential components of UBR-1-regulated signaling consist of the metabolic enzyme GOT-1, vesicular glutamate transporter VGLUT3, and glutamate-gated chloride channel AVR-15. We propose that dysregulation of glutamate homeostasis caused by the absence of UBR-1 may underlie systemic and neurodevelopmental defects in JBS patients.
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