PUBLICATION

Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo.

Authors
Herbert, A.L., Fu, M.M., Drerup, C.M., Gray, R.S., Harty, B.L., Ackerman, S.D., O'Reilly-Pol, T., Johnson, S.L., Nechiporuk, A.V., Barres, B.A., Monk, K.R.
ID
ZDB-PUB-171028-13
Date
2017
Source
Proceedings of the National Academy of Sciences of the United States of America   114: E9153-E9162 (Journal)
Registered Authors
Drerup, Katie (Catherine), Gray, Ryan, Johnson, Stephen L., Monk, Kelly, Nechiporuk, Alex, O'Reilly-Pol, Thomas
Keywords
dynactin, dynein, mRNA transport, myelination, oligodendrocytes
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Axons/pathology
  • Biological Transport
  • Cell Proliferation/genetics
  • Cells, Cultured
  • Dynactin Complex/genetics
  • Dynactin Complex/metabolism*
  • Dyneins/genetics
  • Dyneins/metabolism*
  • Larva
  • Microfilament Proteins/genetics
  • Myelin Basic Protein/genetics*
  • Oligodendroglia/metabolism*
  • Oligodendroglia/pathology
  • RNA, Messenger/metabolism*
  • Rats, Sprague-Dawley
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
(all 20)
PubMed
29073112 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Oligodendrocytes in the central nervous system produce myelin, a lipid-rich, multilamellar sheath that surrounds axons and promotes the rapid propagation of action potentials. A critical component of myelin is myelin basic protein (MBP), expression of which requires anterograde mRNA transport followed by local translation at the developing myelin sheath. Although the anterograde motor kinesin KIF1B is involved in mbp mRNA transport in zebrafish, it is not entirely clear how mbp transport is regulated. From a forward genetic screen for myelination defects in zebrafish, we identified a mutation in actr10, which encodes the Arp11 subunit of dynactin, a critical activator of the retrograde motor dynein. Both the actr10 mutation and pharmacological dynein inhibition in zebrafish result in failure to properly distribute mbp mRNA in oligodendrocytes, indicating a paradoxical role for the retrograde dynein/dynactin complex in anterograde mbp mRNA transport. To address the molecular mechanism underlying this observation, we biochemically isolated reporter-tagged Mbp mRNA granules from primary cultured mammalian oligodendrocytes to show that they indeed associate with the retrograde motor complex. Next, we used live-cell imaging to show that acute pharmacological dynein inhibition quickly arrests Mbp mRNA transport in both directions. Chronic pharmacological dynein inhibition also abrogates Mbp mRNA distribution and dramatically decreases MBP protein levels. Thus, these cell culture and whole animal studies demonstrate a role for the retrograde dynein/dynactin motor complex in anterograde mbp mRNA transport and myelination in vivo.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
nl1TgTransgenic Insertion
    nl15
      Point Mutation
      pt303TgTransgenic Insertion
        sl3TgTransgenic Insertion
          stl83
            Point Mutation
            ue2TgTransgenic Insertion
              ue6TgTransgenic Insertion
                vu16TgTransgenic Insertion
                  vu19TgTransgenic Insertion
                    1 - 9 of 9
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                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    No data available
                    Fish
                    Antibodies
                    No data available
                    Orthology
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    DsRed2EFGDsRed2
                    EGFPEFGEGFP
                    mCherryEFGmCherry
                    mRFPEFGmRFP
                    1 - 4 of 4
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                    Mapping