Presentation/Session Information

Session Information

Session Title: Regeneration and Synaptic Function Session Type: Parallel
Session Location: De Neve Auditorium Session Time: Sat, Jun 27 8:30AM - 11:30AM

Presentation Information

Program Number: 169 Presentation Time: 9:30AM - 9:42AM

Presentation Content

The Johanson-Blizzard Syndrome Ubiquitin Ligase UBR-1 Regulates Glutamate Metabolism and Signaling.Jyothsna Chitturi 1,2, Maria A. Lim* 2, Wesley L. Hung* 2, Anas M. Abdel Rahman 2, John Calarco 3, Renee Baran 4, Xun Huang 5, James Dennis 2, Mei Zhen 1,2. 1)IMS, University of Toronto, Toronto, ON; 2)Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; 3)FAS Center for Systems Biology, Harvard University, Cambridge, MA, USA; 4)Department of Biology, Occidental College, Los Angeles, CA, USA; 5)Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China

*contributed equally

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.




Please note: Abstract shown here should NOT be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.

The Genetics Society of America
9650 Rockville Pike, Bethesda, MD
Phone: 301-634-7300, Fax: 301-634-7079
Questions and Comments: society@genetics-gsa.org