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Akt regulates axon wrapping and myelin sheath thickness in the PNS

Akt regulates axon wrapping and myelin sheath thickness in the PNS
Akt regulates axon wrapping and myelin sheath thickness in the PNS
The signaling pathways that regulate myelination in the PNS remain poorly understood. Phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, activated in Schwann cells by neuregulin and the extracellular matrix, has an essential role in the early events of myelination. Akt/PKB, a key effector of phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, was previously implicated in CNS, but not PNS myelination. Here we demonstrate that Akt plays a crucial role in axon ensheathment and in the regulation of myelin sheath thickness in the PNS. Pharmacological inhibition of Akt in DRG neuron-Schwann cell cocultures dramatically decreased MBP and P0 levels and myelin sheath formation without affecting expression of Krox20/Egr2, a key transcriptional regulator of myelination. Conversely, expression of an activated form of Akt in purified Schwann cells increased expression of myelin proteins, but not Krox20/Egr2, and the levels of activated Rac1. Transgenic mice expressing a membrane-targeted, activated form of Akt under control of the 2?,3?-cyclic nucleotide 3?-phosphodiesterase promoter, exhibited thicker PNS and CNS myelin sheaths, and PNS myelin abnormalities, such as tomacula and myelin infoldings/outfoldings, centered around the paranodes and Schmidt Lanterman incisures. These effects were corrected by rapamycin treatment in vivo. Importantly, Akt activity in the transgenic mice did not induce myelination of nonmyelinating Schwann cells in the sympathetic trunk or Remak fibers of the dorsal roots, although, in those structures, they wrapped membranes redundantly around axons. Together, our data indicate that Akt is crucial for PNS myelination driving axonal wrapping by unmyelinated and myelinated Schwann cells and enhancing myelin protein synthesis in myelinating Schwann cells.
4506-4521
Domènech-Estévez, Enric
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Baloui, Hasna
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Meng, Xiaosong
e8010d19-3c38-41ba-aa46-94486b690ebd
Zhang, Yanqing
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Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Dupree, Jeff L.
11121d8d-bb4a-4a74-a01f-edc5410e7f8e
Einheber, Steven
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Chrast, Roman
086209bb-74cb-4b52-9424-94a4f1862734
Salzer, James L.
eb156f22-5fff-42b7-9551-c1faa7c768b3
Domènech-Estévez, Enric
7f6ee41b-d8ec-48a8-acd7-35454d98ee61
Baloui, Hasna
b1aa862c-fbe1-445a-970f-431e4a256ca9
Meng, Xiaosong
e8010d19-3c38-41ba-aa46-94486b690ebd
Zhang, Yanqing
15e039af-a559-4290-a6b5-43e3f380af89
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Dupree, Jeff L.
11121d8d-bb4a-4a74-a01f-edc5410e7f8e
Einheber, Steven
e0ce1969-50a4-4c88-a2b2-ad3cfa90e0d2
Chrast, Roman
086209bb-74cb-4b52-9424-94a4f1862734
Salzer, James L.
eb156f22-5fff-42b7-9551-c1faa7c768b3

Domènech-Estévez, Enric, Baloui, Hasna, Meng, Xiaosong, Zhang, Yanqing, Deinhardt, Katrin, Dupree, Jeff L., Einheber, Steven, Chrast, Roman and Salzer, James L. (2016) Akt regulates axon wrapping and myelin sheath thickness in the PNS. Journal of Neuroscience, 36 (16), 4506-4521. (doi:10.1523/JNEUROSCI.3521-15.2016).

Record type: Article

Abstract

The signaling pathways that regulate myelination in the PNS remain poorly understood. Phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, activated in Schwann cells by neuregulin and the extracellular matrix, has an essential role in the early events of myelination. Akt/PKB, a key effector of phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, was previously implicated in CNS, but not PNS myelination. Here we demonstrate that Akt plays a crucial role in axon ensheathment and in the regulation of myelin sheath thickness in the PNS. Pharmacological inhibition of Akt in DRG neuron-Schwann cell cocultures dramatically decreased MBP and P0 levels and myelin sheath formation without affecting expression of Krox20/Egr2, a key transcriptional regulator of myelination. Conversely, expression of an activated form of Akt in purified Schwann cells increased expression of myelin proteins, but not Krox20/Egr2, and the levels of activated Rac1. Transgenic mice expressing a membrane-targeted, activated form of Akt under control of the 2?,3?-cyclic nucleotide 3?-phosphodiesterase promoter, exhibited thicker PNS and CNS myelin sheaths, and PNS myelin abnormalities, such as tomacula and myelin infoldings/outfoldings, centered around the paranodes and Schmidt Lanterman incisures. These effects were corrected by rapamycin treatment in vivo. Importantly, Akt activity in the transgenic mice did not induce myelination of nonmyelinating Schwann cells in the sympathetic trunk or Remak fibers of the dorsal roots, although, in those structures, they wrapped membranes redundantly around axons. Together, our data indicate that Akt is crucial for PNS myelination driving axonal wrapping by unmyelinated and myelinated Schwann cells and enhancing myelin protein synthesis in myelinating Schwann cells.

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Accepted/In Press date: 2 March 2016
e-pub ahead of print date: 20 April 2016
Organisations: Biomedicine

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Local EPrints ID: 390807
URI: http://eprints.soton.ac.uk/id/eprint/390807
PURE UUID: 601d3bf5-ff9b-4959-8107-28150d43bd80
ORCID for Katrin Deinhardt: ORCID iD orcid.org/0000-0002-6473-5298

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Date deposited: 07 Apr 2016 11:48
Last modified: 15 Mar 2024 03:45

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Contributors

Author: Enric Domènech-Estévez
Author: Hasna Baloui
Author: Xiaosong Meng
Author: Yanqing Zhang
Author: Jeff L. Dupree
Author: Steven Einheber
Author: Roman Chrast
Author: James L. Salzer

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