Cargando…
PI(3,5)P(2) biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms
Proper development of the CNS axon-glia unit requires bi-directional communication between axons and oligodendrocytes (OLs). We show that the signaling lipid phosphatidylinositol-3,5-bisphosphate [PI(3,5)P(2)] is required in neurons and in OLs for normal CNS myelination. In mice, mutations of Fig4,...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889328/ https://www.ncbi.nlm.nih.gov/pubmed/27008179 http://dx.doi.org/10.7554/eLife.13023 |
_version_ | 1782434973377101824 |
---|---|
author | Mironova, Yevgeniya A Lenk, Guy M Lin, Jing-Ping Lee, Seung Joon Twiss, Jeffery L Vaccari, Ilaria Bolino, Alessandra Havton, Leif A Min, Sang H Abrams, Charles S Shrager, Peter Meisler, Miriam H Giger, Roman J |
author_facet | Mironova, Yevgeniya A Lenk, Guy M Lin, Jing-Ping Lee, Seung Joon Twiss, Jeffery L Vaccari, Ilaria Bolino, Alessandra Havton, Leif A Min, Sang H Abrams, Charles S Shrager, Peter Meisler, Miriam H Giger, Roman J |
author_sort | Mironova, Yevgeniya A |
collection | PubMed |
description | Proper development of the CNS axon-glia unit requires bi-directional communication between axons and oligodendrocytes (OLs). We show that the signaling lipid phosphatidylinositol-3,5-bisphosphate [PI(3,5)P(2)] is required in neurons and in OLs for normal CNS myelination. In mice, mutations of Fig4, Pikfyve or Vac14, encoding key components of the PI(3,5)P(2) biosynthetic complex, each lead to impaired OL maturation, severe CNS hypomyelination and delayed propagation of compound action potentials. Primary OLs deficient in Fig4 accumulate large LAMP1(+) and Rab7(+) vesicular structures and exhibit reduced membrane sheet expansion. PI(3,5)P(2) deficiency leads to accumulation of myelin-associated glycoprotein (MAG) in LAMP1(+)perinuclear vesicles that fail to migrate to the nascent myelin sheet. Live-cell imaging of OLs after genetic or pharmacological inhibition of PI(3,5)P(2) synthesis revealed impaired trafficking of plasma membrane-derived MAG through the endolysosomal system in primary cells and brain tissue. Collectively, our studies identify PI(3,5)P(2) as a key regulator of myelin membrane trafficking and myelinogenesis. DOI: http://dx.doi.org/10.7554/eLife.13023.001 |
format | Online Article Text |
id | pubmed-4889328 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-48893282016-06-02 PI(3,5)P(2) biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms Mironova, Yevgeniya A Lenk, Guy M Lin, Jing-Ping Lee, Seung Joon Twiss, Jeffery L Vaccari, Ilaria Bolino, Alessandra Havton, Leif A Min, Sang H Abrams, Charles S Shrager, Peter Meisler, Miriam H Giger, Roman J eLife Neuroscience Proper development of the CNS axon-glia unit requires bi-directional communication between axons and oligodendrocytes (OLs). We show that the signaling lipid phosphatidylinositol-3,5-bisphosphate [PI(3,5)P(2)] is required in neurons and in OLs for normal CNS myelination. In mice, mutations of Fig4, Pikfyve or Vac14, encoding key components of the PI(3,5)P(2) biosynthetic complex, each lead to impaired OL maturation, severe CNS hypomyelination and delayed propagation of compound action potentials. Primary OLs deficient in Fig4 accumulate large LAMP1(+) and Rab7(+) vesicular structures and exhibit reduced membrane sheet expansion. PI(3,5)P(2) deficiency leads to accumulation of myelin-associated glycoprotein (MAG) in LAMP1(+)perinuclear vesicles that fail to migrate to the nascent myelin sheet. Live-cell imaging of OLs after genetic or pharmacological inhibition of PI(3,5)P(2) synthesis revealed impaired trafficking of plasma membrane-derived MAG through the endolysosomal system in primary cells and brain tissue. Collectively, our studies identify PI(3,5)P(2) as a key regulator of myelin membrane trafficking and myelinogenesis. DOI: http://dx.doi.org/10.7554/eLife.13023.001 eLife Sciences Publications, Ltd 2016-03-23 /pmc/articles/PMC4889328/ /pubmed/27008179 http://dx.doi.org/10.7554/eLife.13023 Text en © 2016, Mironova et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Neuroscience Mironova, Yevgeniya A Lenk, Guy M Lin, Jing-Ping Lee, Seung Joon Twiss, Jeffery L Vaccari, Ilaria Bolino, Alessandra Havton, Leif A Min, Sang H Abrams, Charles S Shrager, Peter Meisler, Miriam H Giger, Roman J PI(3,5)P(2) biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title | PI(3,5)P(2) biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_full | PI(3,5)P(2) biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_fullStr | PI(3,5)P(2) biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_full_unstemmed | PI(3,5)P(2) biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_short | PI(3,5)P(2) biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_sort | pi(3,5)p(2) biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889328/ https://www.ncbi.nlm.nih.gov/pubmed/27008179 http://dx.doi.org/10.7554/eLife.13023 |
work_keys_str_mv | AT mironovayevgeniyaa pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT lenkguym pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT linjingping pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT leeseungjoon pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT twissjefferyl pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT vaccariilaria pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT bolinoalessandra pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT havtonleifa pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT minsangh pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT abramscharless pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT shragerpeter pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT meislermiriamh pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms AT gigerromanj pi35p2biosynthesisregulatesoligodendrocytedifferentiationbyintrinsicandextrinsicmechanisms |