Dlg1-PTEN Interaction Regulates Myelin Thickness to Prevent Damaging Peripheral Nerve Overmyelination

Cotter, Laurent; Özçelik, Murat; Jacob, Claire; Pereira, Jorge A.; Locher, Veronica; Baumann, Reto; Relvas, João B.; Suter, Ueli; Tricaud, Nicolas

doi:10.1126/science.1187735

Cited by 171 publications

(167 citation statements)

References 32 publications

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“…Indeed, many key polarity proteins are expressed in SCs (24), making it increasingly clear that molecular mechanisms used to establish polarity in epithelia are also operant in SCs. Importantly, manipulation of these proteins does not result in global SC dysfunction, but rather in attenuated myelin thickness and in specific defects of myelin formation (24,41). For example, focal myelin protrusions with similarities to those we observed in Sirt2-SCKO mutants (Fig.…”

Section: Discussionmentioning

confidence: 74%

“…On the basis of the identified interaction between Par-3 and the p75 NTR receptor (23), this deficit was mechanistically attributed to mislocalization of p75 NTR at the axo-glial junction, resulting in failed BDNF signal transduction at this site, which is crucial for myelination. Additionally, the polarity proteins Pals1 and Dlg1 also play a role in myelin assembly in vivo (24,41). Indeed, many key polarity proteins are expressed in SCs (24), making it increasingly clear that molecular mechanisms used to establish polarity in epithelia are also operant in SCs.…”

Section: Discussionmentioning

confidence: 99%

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Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Beirowski¹,

Gustin

Armour

et al. 2011

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

151

119

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The formation of myelin by Schwann cells (SCs) occurs via a series of orchestrated molecular events. We previously used global expression profiling to examine peripheral nerve myelination and identified the NAD + -dependent deacetylase Sir-two-homolog 2 (Sirt2) as a protein likely to be involved in myelination. Here, we show that Sirt2 expression in SCs is correlated with that of structural myelin components during both developmental myelination and remyelination after nerve injury. Transgenic mice lacking or overexpressing Sirt2 specifically in SCs show delays in myelin formation. In SCs, we found that Sirt2 deacetylates Par-3, a master regulator of cell polarity. The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex signaling component aPKC, thereby regulating myelin formation. These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity.neuropathy | sirtuin | acetylation M yelinating Schwann cells (SCs) perform a range of tasks required for correct function of the peripheral nervous system (PNS). In addition to ensuring normal locomotion and sensation and providing trophic support of axons (1), they control regenerative and reparative responses in peripheral nerves (2). These functions are tightly linked to the ability of differentiated SCs to intimately associate with axons and ensheath them with compact myelin. Various pathways in SCs have been identified that are crucial for this process including neuronal growth factors, cell adhesion, and a number of second messenger systems (3). These pathways are interrelated with strict temporal control of key transcription factors, collectively responsible for up-regulation of genes critical for structural assembly of myelin (3, 4).Metabolic derangements contribute to a major class of conditions in which SC function is impaired. For example, numerous studies indicate that nerve regeneration and myelination after injury are impaired in diabetic neuropathy (5-8). Moreover, SC myelination can be altered by changes in nutrition (9, 10). These findings give rise to the idea that abnormal metabolic conditions could lead to aberrant myelination via abnormalities in SC function. We previously identified Sir-two-homolog 2 (Sirt2) in gene expression profiling experiments as a putative myelinationassociated protein on the basis of the similarity of its expression to that of mRNAs encoding structural myelin proteins during periods of myelin formation (11). Sirt2 is a member of the conserved sirtuin family of NAD + -dependent deacetylases that modulate cellular processes in accord with the metabolic state (12, 13). Depending on the cellular context and tissue type, Sirt2 is reported to deacetylate α-tubulin (14, 15), control cell division (16), regulate adipocyte differentiation through FOXO1 (17), and alter gene expression via the deacetylation of histone H4 (18) among other functions.Here, we demonstrate that norm...

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Beirowski¹,

Gustin

Armour

et al. 2011

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

151

119

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“…Further supporting evidence derives from the analysis of mTor mutant mice that arrest myelin growth prematurely and that form thin myelin (Sherman et al, 2012). Dlg1-PTEN interactions were also reported to control the end of myelination and thus myelin thickness, and might impinge on the control of protein synthesis (Cotter et al, 2010). …”

Section: Rates Of Protein Synthesis Control the End Of Myelination Anmentioning

confidence: 98%

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Birchmeier

Bennett

2016

Current Topics in Developmental Biology

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Myelin is essential for rapid and accurate conduction of electrical impulses by axons in the central and peripheral nervous system. Myelin is formed in the early postnatal period, and developmental myelination in the peripheral nervous system (PNS) depends on axonal signals provided by Nrg1/ErbB receptors. In addition, Nrg1 is required for effective nerve repair and remyelination in adulthood. We discuss here similarities and differences in Nrg1/ErbB functions in developmental myelination and remyelination after nerve injury.

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“…The major outcomes of the loss‐ and gain‐of‐function studies on the roles of mTORC1 and the upstream PI3K‐Akt and Mek‐Erk1/2 pathways in PNS and CNS myelination are summarized (Beirowski et al, 2017; Bercury et al, 2014; Carson et al, 2015; Cotter et al, 2010; Domenech‐Estevez et al, 2016; Figlia et al, 2017; Flores et al, 2008; Fyffe‐Maricich, Karlo, Landreth, & Miller, 2011; Fyffe‐Maricich, Schott, Karl, Krasno, & Miller, 2013; Goebbels et al, 2010, 2012; Ishii, Furusho, & Bansal, 2013; Ishii, Furusho, Dupree, & Bansal, 2016; Jeffries et al, 2016; Jiang et al, 2016; Lebrun‐Julien et al, 2014; Napoli et al, 2012; Newbern et al, 2011; Norrmén et al, 2014; Sheean et al, 2014; Sherman et al, 2012; Wahl et al, 2014; Zou et al, 2011, 2014)…”

Section: Myelination and Mtormentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

Self Cite

136

120

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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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Dlg1-PTEN Interaction Regulates Myelin Thickness to Prevent Damaging Peripheral Nerve Overmyelination

Cited by 171 publications

References 32 publications

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Myelination and mTOR

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