Elevated phosphatidylinositol 3,4,5-trisphosphate in glia triggers cell-autonomous membrane wrapping and myelination.
In the developing nervous system, constitutive activation of the AKT/mTOR (mammalian target of rapamycin) pathway in myelinating glial cells is associated with hypermyelination of the brain, but is reportedly insufficient to drive myelination by Schwann cells. We have hypothesized that it requires additional mechanisms downstream of NRG1/ErbB signaling to trigger myelination in the peripheral nervous system. Here, we demonstrate that elevated levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) have developmental effects on both oligodendrocytes and Schwann cells. By generating conditional mouse mutants, we found that Pten-deficient Schwann cells are enhanced in number and can sort and myelinate axons with calibers well below 1 microm. Unexpectedly, mutant glial cells also spirally enwrap C-fiber axons within Remak bundles and even collagen fibrils, which lack any membrane surface. Importantly, PIP3-dependent hypermyelination of central axons, which is observed when targeting Pten in oligodendrocytes, can also be induced after tamoxifen-mediated Cre recombination in adult mice. We conclude that it requires distinct PIP3 effector mechanisms to trigger axonal wrapping. That myelin synthesis is not restricted to early development but can occur later in life is relevant to developmental disorders and myelin disease.
Goebbels
Sandra
S
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Göttingen, Germany. sgoebbels@em.mpg.de or nave@em.mpg.de
Oltrogge
Jan H
JH
Kemper
Robert
R
Heilmann
Ingo
I
Bormuth
Ingo
I
Wolfer
Susanne
S
Wichert
Sven P
SP
Möbius
Wiebke
W
Liu
Xin
X
Lappe-Siefke
Corinna
C
Rossner
Moritz J
MJ
Groszer
Matthias
M
Suter
Ueli
U
Frahm
Jens
J
Boretius
Susann
S
Nave
Klaus-Armin
KA
D000375:Aging; D000818:Animals; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D001921:Brain / Q000502:physiology / Q000648:ultrastructure; D002452:Cell Count; D003094:Collagen / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009413:Nerve Fibers, Myelinated / Q000502:physiology / Q000648:ultrastructure; D009457:Neuroglia / Q000502:physiology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000502:physiology* / Q000648:ultrastructure; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D012583:Schwann Cells / Q000502:physiology* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000502:physiology / Q000648:ultrastructure
D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D003094:Collagen; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse