Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system

Heller, Bradley A.; Ghidinelli, Monica; Voelkl, Jakob; Einheber, Steven; Smith, Ryan J.; Grund, Ethan M.; Morahan, Grant; Chandler, David; Kalaydjieva, Luba; Giancotti, Filippo G.; King, R. H. M.; Fejes-Toth, Aniko Naray; Fejes-Toth, Gerard; Feltri, M. Laura; Läng, Florian; Salzer, James L.

doi:10.1083/jcb.201307057

Cited by 65 publications

(87 citation statements)

References 94 publications

(145 reference statements)

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“…Rather, an almost complete absence was clearly evident from day 7 postcrush in WT animals, whereas expression of the signal transduction factor was prolonged until much later at day 28 in the null animals. It is possible that the prolonged presence of AKT in the injured αBC −/− animals negatively influenced remyelination similar to that seen in the study by Heller et al (49).…”

Section: Discussionsupporting

confidence: 73%

“…The PI3K-AKT pathway has been implicated in PNS remyelination (34), whereby increased levels or deficiency promoted or inhibited both PNS and CNS myelination (34). However, recent work by Heller et al (49) noted that the PI3K pathway, which can act via AKT, has differing effects on Schwann cell myelination depending on its temporal expression. Early presence was associated with myelination via AKT/mTOR, but later expression via laminin activation negatively affected myelination.…”

Section: Discussionmentioning

confidence: 99%

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AlphaB-crystallin regulates remyelination after peripheral nerve injury

Lim

Nakanishi

Hoghooghi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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AlphaB-crystallin (αBC) is a small heat shock protein that is constitutively expressed by peripheral nervous system (PNS) axons and Schwann cells. To determine what role this crystallin plays after peripheral nerve damage, we found that loss of αBC impaired remyelination, which correlated with a reduced presence of myelinating Schwann cells and increased numbers of nonmyelinating Schwann cells. The heat shock protein also seems to regulate the cross-talk between Schwann cells and axons, because expected changes in neuregulin levels and ErbB2 receptor expression after PNS injury were disrupted in the absence of αBC. Such dysregulations led to defects in conduction velocity and motor and sensory functions that could be rescued with therapeutic application of the heat shock protein in vivo. Altogether, these findings show that αBC plays an important role in regulating Wallerian degeneration and remyelination after PNS injury.T he robust regenerative capacity of the damaged peripheral nervous system (PNS) is partly determined by cellular and molecular events that occur in the nerve segment distal to the injury site (1). For instance, during Wallerian degeneration, influx of calcium into the damaged nerve within 12-24 h of PNS injury activates proteases (2) that result in cytoskeletal breakdown and subsequent disintegration of the axon membrane. This axon degeneration is then followed by breakdown of the myelin sheath within 2 d (3). Schwann cells, the glial cells that characterize the PNS, subsequently undergo a number of reactive physiological changes that benefit the damaged axon. Within 48 h of peripheral nerve damage, myelinating Schwann cells decrease their expression of myelin proteins, such as myelin basic protein (MBP), peripheral myelin protein 22, and protein 0 (P0) (4), and along with their nonmyelinating counterparts, revert to a nonmyelinating phenotype (4). At ∼3-4 d postinjury, the dedifferentiated Schwann cells proliferate (5-7) and align within the basal lamina to form bands of Büngner that provide a structural and trophic supportive substrate for regenerating axons. These Schwann cells secrete neurotrophic factors that provide trophic sustenance to damaged neurons until they reestablish contact with their targets (8) and produce extracellular matrix molecules that encourage and guide outgrowing axons (9), whereas secretion of chemokines is thought to mediate the infiltration of blood-derived macrophages, which along with Schwann cells, phagocytose myelin debris and its associated axon growth inhibitors (9). Finally, based on the level of neuregulin 1 Types I and III on Schwann cells and axons, respectively, and their binding to their cognate receptors ErbB2/ ErbB3 on Schwann cells, these glia will revert to a myelinating or ensheathing phenotype on contact with regrowing axons (10). Altogether, these morphological and physiological changes in Schwann cells create an environment that encourages longdistance axon growth.In humans, however, regrowth of damaged peripheral nerves is often incomplete, wh...

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

AlphaB-crystallin regulates remyelination after peripheral nerve injury

Lim

Nakanishi

Hoghooghi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…First, under normal physiological conditions, mTORC1 activity in SCs is high prior to the onset of myelination and declines to lower levels as cells progress from the promyelinating stage further (Beirowski, Wong, Babetto, & Milbrandt, 2017; Figlia, Norrmen, Pereira, Gerber, & Suter, 2017; Heller et al, 2014). Second, mTORC1 hyperactivation due to SC‐specific deletion of TSC1 or the negative regulator of PI3K‐Akt signaling PTEN delayed onset of myelination (Beirowski et al, 2017; Figlia et al, 2017), while even higher mTORC1 activity following deletion of TSC2 persistently arrested onset of myelination (Beirowski et al, 2017).…”

Section: Myelination and Mtormentioning

confidence: 99%

“…NRG1 activates both the PI3K‐Akt and Mek‐Erk1/2 pathways, and more downstream activation of mTORC1 was also observed upon in vitro stimulation of SCs with NRG1 (Figlia et al, 2017). Furthermore, loss of NRG1 stimulation strongly reduced mTORC1 activity in SCs (Heller et al, 2014), indicating that other ligand‐receptor interactions than NRG1 signaling, such as the extracellular matrix‐binding integrins, are probably minor contributors to mTORC1 activation in SCs.…”

Section: Myelination and Mtormentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

128

107

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Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.

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“…Consistent with their proposed role in transport, Cajal bands are enriched in a large array of cytoskeletal proteins, including microtubules, intermediate filaments, and an actin/spectrin complex (Susuki et al 2011;Kidd et al 2013;Walko et al 2013). They also represent sites of localized protein synthesis (Gould and Mattingly 1990), and intracellular signaling via laminin receptors (Heller et al 2014). Based on their enrichment in caveolae Figure 2.…”

Section: Organization and Polarity Of The Pns Myelin Sheathmentioning

confidence: 86%

Schwann Cell Myelination

Salzer

2015

Cold Spring Harb Perspect Biol

Self Cite

274

272

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Myelinated nerve fibers are essential for the rapid propagation of action potentials by saltatory conduction. They form as the result of reciprocal interactions between axons and Schwann cells. Extrinsic signals from the axon, and the extracellular matrix, drive Schwann cells to adopt a myelinating fate, whereas myelination reorganizes the axon for its role in conduction and is essential for its integrity. Here, we review our current understanding of the development, molecular organization, and function of myelinating Schwann cells. Recent findings into the extrinsic signals that drive Schwann cell myelination, their cognate receptors, and the downstream intracellular signaling pathways they activate will be described. Together, these studies provide important new insights into how these pathways converge to activate the transcriptional cascade of myelination and remodel the actin cytoskeleton that is critical for morphogenesis of the myelin sheath.

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Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system

Abstract: Functionally and spatially distinct PI 3-K pathways act either early to promote myelination downstream of axonal Neuregulin1 or late to inhibit myelination downstream of α6β4 integrin and Sgk1.

Cited by 65 publications

References 94 publications

AlphaB-crystallin regulates remyelination after peripheral nerve injury

AlphaB-crystallin regulates remyelination after peripheral nerve injury

Myelination and mTOR

Schwann Cell Myelination

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