Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Australia; Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Australia; Centre for Dynamic Imaging, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Andrew Kueh
Department of Medical Biology, The University of Melbourne, Parkville, Australia; Melbourne Advanced Genome Editing Centre, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Australia; Histology Facility, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Australia; Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Georgios Kastrappis
Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Australia; Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Australia; Centre for Dynamic Imaging, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; The Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
David Komander
Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Australia
Grant Dewson
Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Australia
Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Australia; Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
ZRANB1 (human Trabid) missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We have characterized these patient mutations in cells and mice to identify a key role for Trabid in the regulation of neurite growth. One of the patient mutations flanked the catalytic cysteine of Trabid and its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, but failed to bind STRIPAK, a large multiprotein assembly implicated in cytoskeleton organization and neural development. Zranb1 knock-in mice harboring either of these patient mutations exhibited reduced neuronal and glial cell densities in the brain and a motor deficit consistent with fewer dopaminergic neurons and projections. Mechanistically, both DUB-impaired and STRIPAK-binding-deficient Trabid variants impeded the trafficking of adenomatous polyposis coli (APC) to microtubule plus-ends. Consequently, the formation of neuronal growth cones and the trajectory of neurite outgrowth from mutant midbrain progenitors were severely compromised. We propose that STRIPAK recruits Trabid to deubiquitylate APC, and that in cells with mutant Trabid, APC becomes hyperubiquitylated and mislocalized causing impaired organization of the cytoskeleton that underlie the neuronal and developmental phenotypes.
