Constitutively Active Akt Induces Enhanced Myelination in the CNS

Flores, Ana I.; Narayanan, S. Priya; Morse, Emily N.; Shick, H. Elizabeth; Yin, Xiaoju; Kidd, Grahame J.; Avila, Robin; Kirschner, Daniel A.; Macklin, Wendy B.

doi:10.1523/jneurosci.0150-08.2008

Cited by 317 publications

(377 citation statements)

References 55 publications

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“…Among them, the PI3K/Akt pathway appears to be a major effecter of NRG1 to regulate myelination (16). Having demonstrated that Erbin regulates ErbB2 stability and internalization, we next tested if Erbin deficiency alters intracellular signaling by NRG1.…”

Section: Resultsmentioning

confidence: 99%

“…Disruption of NRG1/ErbB signaling by a dominant negative approach led to deficits in myelinating and nonmyelinating SCs (14,15). Intracellularly, NRG1 stimulates various cascades including the PI3K/Akt pathway that have been implicated in myelinaton (16). Although much is known about the role of NRG1 signaling in SC myelination, less is known about its regulatory mechanisms.…”

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confidence: 99%

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Erbin regulates NRG1 signaling and myelination

Tao

Dai

Liu

et al. 2009

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

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Neuregulin 1 (NRG1) plays a critical role in myelination. However, little is known about regulatory mechanisms of NRG1 signaling. We show here that Erbin, a protein that contains leucine-rich repeats (LRR) and a PSD95-Dlg-Zol (PDZ) domain and that interacts specifically with ErbB2, is necessary for NRG1 signaling and myelination of peripheral nervous system (PNS). In Erbin null mice, myelinated axons were hypomyelinated with reduced expression of P0, a marker of mature myelinating Schwann cells (SCs), whereas unmyelinated axons were aberrantly ensheathed in Remak bundles, with increased numbers of axons in the bundles and in pockets. The morphological deficits were associated with decreased nerve conduction velocity and increased sensory threshold to mechanistic stimulation. These phenotypes were duplicated in erbin ⌬C/⌬C mice, in which Erbin lost the PDZ domain to interact with ErbB2. Moreover, ErbB2 was reduced at protein levels in both Erbin mutant sciatic nerves, and ErbB2 became unstable and NRG1 signaling compromised when Erbin expression was suppressed. These observations indicate a critical role of Erbin in myelination and identify a regulatory mechanism of NRG1 signaling. Our results suggest that Erbin, via the PDZ domain, binds to and stabilizes ErbB2, which is necessary for NRG1 signaling that has been implicated in tumorigenesis, heart development, and neural function.ErbB2 ͉ PDZ ͉ protein stability ͉ Schwann cells ͉ Akt M yelin sheath wraps axons to ensure the velocity and timing of action potential propagation and insulates neuronal activity. Impaired myelin formation and maintenance have been implicated in various neurological and psychiatric disorders including schizophrenia, multiple sclerosis, and Charcot-Marie-Tooth neuropathy disease (1, 2). Myelination is a tightly controlled, complex process. In the peripheral nervous system (PNS), neuregulin 1 (NRG1) has emerged as a key axon-derived factor that regulates myelination. Disruption of NRG1 signaling by ablating either the EGF domain that is contained in all isoforms or type III isoform leads to an almost complete loss of SCs and of the sensory and motor neurons that they support (3, 4). Recent studies have suggested that the level of NRG1 in the axon is critical for myelination (5, 6).NRG1 acts by stimulating a family of single transmembrane receptor tyrosine kinases called ErbB proteins (1). Although NRG1 was isolated as a ''ligand'' to activate ErbB2, it does not interact with the receptor (7). However, ErbB3 can bind NRG1 but its homodimers are catalytically inactive, indicating impaired kinase function (8). Therefore, ErbB2 and ErbB3, major ErbB proteins in SCs, need to form heterodimers with each other to be functional (9). This notion is supported by mouse genetic studies that mutation of NRG1, ErbB2, or ErbB3 genes causes severe deficits of peripheral neurons and SCs (3, 4, 10-13). Disruption of NRG1/ErbB signaling by a dominant negative approach led to deficits in myelinating and nonmyelinating SCs (14,15). Intracellularly, NRG1 stimu...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Erbin regulates NRG1 signaling and myelination

Tao

Dai

Liu

et al. 2009

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

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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%

“…mTORC1‐independent targets of PI3K‐Akt could have important functions also during OL myelination. While deletion of TSC1 or TSC2 in OLs (i.e., mTORC1 hyperactivation, but suppression of PI3K‐Akt) resulted in CNS hypomyelination and OL death (Jiang et al, 2016), expression of constitutively active Akt, or deletion of the PI3K‐Akt inhibitor PTEN (i.e., hyperactivation of both mTORC1 and PI3K‐Akt), caused marked radial hypermyelination (Domenech‐Estevez et al, 2016; Flores et al, 2008; Goebbels et al, 2010). Since Akt can promote cell survival (Manning & Toker, 2017), Akt‐dependent but mTORC1‐independent survival pathways may be required during OL myelination.…”

Section: Myelination and Mtormentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

128

104

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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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“…To assess Ind-Cl effects on the potentially BDNF-mediated PI3K/Akt/mTOR pathway [also modulated by DPN (6,(19)(20)(21)] in EAE mice, CC homogenates were probed for relevant proteins Fig. 3.…”

Section: Ind-clmentioning

confidence: 99%

Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis

Moore¹,

Khalaj

Kumar

et al. 2014

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

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Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) β agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind-Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet-induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment.M ultiple sclerosis (MS) is an autoimmune, demyelinating, and neurodegenerative disease of the central nervous system (CNS) that affects 2-2.5 million people worldwide. Currently approved MS drugs reduce relapse rates but fail to reverse or prevent neurodegeneration and disability progression. Disease-modifying drugs capable of restoring neuronal function via axon remyelination (RM) represent a major unmet goal for MS therapeutics.Oligodendrocyte (OL) progenitor cells (OPCs) are responsible for remyelinating axons, make up at least 3% of all white matter cells, and are present in and around MS lesions; however, they remain largely quiescent in the adult CNS (1). Although endogenous RM can occur in patients with MS, as evidenced by shadow plaques, it is short-lived, incomplete, and relatively ineffective (2). Transition to progressive MS is characterized by increased axon loss, which correlates with RM failure (3). Hence, a treatment that stimulates endogenous OPCs to differentiate and remyelinate axons would reduce axon degeneration and restore neuronal function.Experimental autoimmune encephalomyelitis (EAE) affords researchers an in-depth, mechanistic understanding of immunemediated, demyelinating neurodegeneration and anti-inflammatory effects of currently approved MS drugs. Our recent work has demonstrated promising neuroprotective effects of the estrogen receptor (ER) β agonist 2,3-bis(4-hydroxyphenyl)propionitrile...

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Constitutively Active Akt Induces Enhanced Myelination in the CNS

Cited by 317 publications

References 55 publications

Erbin regulates NRG1 signaling and myelination

Erbin regulates NRG1 signaling and myelination

Myelination and mTOR

Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis

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