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

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 follow...

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Autores principales: Herbert, Amy L., Fu, Meng-meng, Drerup, Catherine M., Gray, Ryan S., Harty, Breanne L., Ackerman, Sarah D., O’Reilly-Pol, Thomas, Johnson, Stephen L., Nechiporuk, Alex V., Barres, Ben A., Monk, Kelly R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664533/
https://www.ncbi.nlm.nih.gov/pubmed/29073112
http://dx.doi.org/10.1073/pnas.1711088114
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author Herbert, Amy L.
Fu, Meng-meng
Drerup, Catherine M.
Gray, Ryan S.
Harty, Breanne L.
Ackerman, Sarah D.
O’Reilly-Pol, Thomas
Johnson, Stephen L.
Nechiporuk, Alex V.
Barres, Ben A.
Monk, Kelly R.
author_facet Herbert, Amy L.
Fu, Meng-meng
Drerup, Catherine M.
Gray, Ryan S.
Harty, Breanne L.
Ackerman, Sarah D.
O’Reilly-Pol, Thomas
Johnson, Stephen L.
Nechiporuk, Alex V.
Barres, Ben A.
Monk, Kelly R.
author_sort Herbert, Amy L.
collection PubMed
description 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.
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spelling pubmed-56645332017-11-03 Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo Herbert, Amy L. Fu, Meng-meng Drerup, Catherine M. Gray, Ryan S. Harty, Breanne L. Ackerman, Sarah D. O’Reilly-Pol, Thomas Johnson, Stephen L. Nechiporuk, Alex V. Barres, Ben A. Monk, Kelly R. Proc Natl Acad Sci U S A PNAS Plus 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. National Academy of Sciences 2017-10-24 2017-10-12 /pmc/articles/PMC5664533/ /pubmed/29073112 http://dx.doi.org/10.1073/pnas.1711088114 Text en Freely available online through the PNAS open access option.
spellingShingle PNAS Plus
Herbert, Amy L.
Fu, Meng-meng
Drerup, Catherine M.
Gray, Ryan S.
Harty, Breanne L.
Ackerman, Sarah D.
O’Reilly-Pol, Thomas
Johnson, Stephen L.
Nechiporuk, Alex V.
Barres, Ben A.
Monk, Kelly R.
Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo
title Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo
title_full Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo
title_fullStr Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo
title_full_unstemmed Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo
title_short Dynein/dynactin is necessary for anterograde transport of Mbp mRNA in oligodendrocytes and for myelination in vivo
title_sort dynein/dynactin is necessary for anterograde transport of mbp mrna in oligodendrocytes and for myelination in vivo
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664533/
https://www.ncbi.nlm.nih.gov/pubmed/29073112
http://dx.doi.org/10.1073/pnas.1711088114
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