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

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.
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
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
29073112 Full text @ Proc. Natl. Acad. Sci. USA
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
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes