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 treatmentin 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.


CONCLUSIONS
Although the role of the key serine/threonine kinase Akt in promoting CNS myelination has been demonstrated, its role in the PNS has not been established and remains uncertain. This work reveals that Akt controls several key steps of the PNS myelination. First, its activity promotes membrane production and axonal wrapping independent of a transcriptional effect. In myelinated axons, it also enhances myelin thickness through the mTOR pathway. Finally, sustained Akt activation in Schwann cells leads to hypermyelination/dysmyelination, mimicking some features present in neuropathies, such as hereditary neuropathy with liability to pressure palsies or demyelinating forms of Charcot-Marie-Tooth disease. Together, these data demonstrate the role of Akt in regulatory mechanisms underlying axonal wrapping and myelination in the PNS.
Neuroscience Institute and Departments of Neuroscience and Physiology and Neurology, New York University-Langone Medical Center, New York, New York 10016, Departments of Neuroscience and Clinical Neuroscience, Karolinska Institutet, Stockholm 17177, Sweden, enric.domenech-estevez@ki.se james.salzer@nyumc.org.
Enric
E
Domènech-Estévez
Neuroscience Institute and Departments of Neuroscience and Physiology and Neurology, New York University-Langone Medical Center, New York, New York 10016, Departments of Neuroscience and Clinical Neuroscience, Karolinska Institutet, Stockholm 17177, Sweden.
Hasna
H
Baloui
Neuroscience Institute and Departments of Neuroscience and Physiology and Neurology, New York University-Langone Medical Center, New York, New York 10016.
Xiaosong
X
Meng
Neuroscience Institute and Departments of Neuroscience and Physiology and Neurology, New York University-Langone Medical Center, New York, New York 10016.
Yanqing
Y
Zhang
Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom.
Katrin
http://orcid.org/0000-0002-6473-5298
K
Deinhardt
Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, Virginia 23298-0709, and.
Jeff L
http://orcid.org/0000-0002-6235-570X
JL
Dupree
Department of Medical Laboratory Sciences, Hunter College, City University of New York, New York, New York 10010.
Steven
S
Einheber
Departments of Neuroscience and Clinical Neuroscience, Karolinska Institutet, Stockholm 17177, Sweden.
Roman
R
Chrast
Neuroscience Institute and Departments of Neuroscience and Physiology and Neurology, New York University-Langone Medical Center, New York, New York 10016, enric.domenech-estevez@ki.se james.salzer@nyumc.org.
James L
JL
Salzer
D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D051058:Oncogene Protein v-akt / Q000502:physiology*; D010525:Peripheral Nerves / Q000502:physiology / Q000648:ultrastructure; D017933:Peripheral Nervous System / Q000502:physiology / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000502:physiology* / Q000648:ultrastructure
D051058:Oncogene Protein v-akt
Akt; Schwann cell; mTOR; myelin; transgenic; wrapping