TY - JOUR
T1 - DYNLRB1 is essential for dynein mediated transport and neuronal survival
AU - Terenzio, Marco
AU - Di Pizio, Agostina
AU - Rishal, Ida
AU - Marvaldi, Letizia
AU - Di Matteo, Pierluigi
AU - Kawaguchi, Riki
AU - Coppola, Giovanni
AU - Schiavo, Giampietro
AU - Fisher, Elizabeth M. C.
AU - Fainzilber, Mike
N1 - We thank Nicolas Panayotis for expert guidance and advice with the behavioral assays; Nitzan Korem and Nataliya Okladnikov for excellent technical assistance; Vladmir Kiss for professional microscopy support; Dalia Gordon, Indrek Koppel, Michael Tsoory and Stefanie Alber for helpful comments and advice; Avraham Yaron for the kind gift of the Ai9 mice and Avri Ben-Ze'ev for the kind gift of a β-catenin antibody. We thank the Medical Research Council Mammalian Genetics Unit, Harwell, UK for providing the Dynlrb1tm1a(EUCOMM)Wtsi mice. This work was supported by funding from the European Research Council (Neurogrowth, MF), the Israel Science Foundation (1337/18, MF), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (MF & GC), a Wellcome Trust Senior Investigator Award (107116/Z/15/Z, GS), the European Union's Horizon 2020 Research and Innovation programme (grant agreement 739572, GS), a UK Dementia Research Institute Foundation award (GS), and the Medical Research Council (MRC, to E.M.C.F.). M.T. was supported by a Koshland senior postdoctoral fellowship. M.F. is the incumbent of the Chaya Professorial Chair in Molecular Neuroscience at the Weizmann Institute of Science. Author contributions - M.F. and M.T. designed the study. M.T., A.D.P., I.R., L.M., P.D.M., and R.K. performed experiments and data analyses. R.K. carried out RNA sequencing. M.F., E.M.C.F., G.C., and G.S. supervised research. M.F. and M.T. wrote the initial manuscript draft. All authors revised the manuscript and approved the final version.
PY - 2020/7
Y1 - 2020/7
N2 - The cytoplasmic dynein motor complex transports essential signals and organelles from the cell periphery to the perinuclear region, hence is critical for the survival and function of highly polarized cells such as neurons. Dynein Light Chain Roadblock-Type 1 (DYNLRB1) is thought to be an accessory subunit required for specific cargos, but here we show that it is essential for general dynein-mediated transport and sensory neuron survival. Homozygous Dynlrb1 null mice are not viable and die during early embryonic development. Furthermore, heterozygous or adult knockdown animals display reduced neuronal growth, and selective depletion of Dynlrb1 in proprioceptive neurons compromises their survival. Conditional depletion of Dynlrb1 in sensory neurons causes deficits in several signaling pathways, including β-catenin subcellular localization, and a severe impairment in the axonal transport of both lysosomes and retrograde signaling endosomes. Hence, DYNLRB1 is an essential component of the dynein complex, and given dynein's critical functions in neuronal physiology, DYNLRB1 could have a prominent role in the etiology of human neurodegenerative diseases.
AB - The cytoplasmic dynein motor complex transports essential signals and organelles from the cell periphery to the perinuclear region, hence is critical for the survival and function of highly polarized cells such as neurons. Dynein Light Chain Roadblock-Type 1 (DYNLRB1) is thought to be an accessory subunit required for specific cargos, but here we show that it is essential for general dynein-mediated transport and sensory neuron survival. Homozygous Dynlrb1 null mice are not viable and die during early embryonic development. Furthermore, heterozygous or adult knockdown animals display reduced neuronal growth, and selective depletion of Dynlrb1 in proprioceptive neurons compromises their survival. Conditional depletion of Dynlrb1 in sensory neurons causes deficits in several signaling pathways, including β-catenin subcellular localization, and a severe impairment in the axonal transport of both lysosomes and retrograde signaling endosomes. Hence, DYNLRB1 is an essential component of the dynein complex, and given dynein's critical functions in neuronal physiology, DYNLRB1 could have a prominent role in the etiology of human neurodegenerative diseases.
UR - http://www.scopus.com/inward/record.url?scp=85082710871&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2020.104816
DO - 10.1016/j.nbd.2020.104816
M3 - مقالة
C2 - 32088381
SN - 0969-9961
VL - 140
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 104816
ER -