Promotion of Peripheral Nerve Regeneration by Stimulation of the Extracellular Signal‐Regulated Kinase (ERK) Pathway

Hausott, Barbara; Klimaschewski, Lars

doi:10.1002/ar.24126

Cited by 40 publications

(30 citation statements)

References 87 publications

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“…Disturbed activation of the PI3K/Akt/ and Ras/Erk pathways are oncogenic, enhancing the growth, survival, and metabolism of cancer cells (Jokinen and Koivunen, 2015). PI3K/Akt and Ras/Erk signaling pathways are also key mediators for neuronal survival and several aspects of neurite outgrowth, including cell skeleton reorganization and stabilization, neurite branching and extension, and axon formation (Frebel and Wiese, 2006;Read and Gorman, 2009;Hausott and Klimaschewski, 2019). Mammalian target of rapamycin (mTOR) is one of the major downstream effectors of PI3K/Akt and Ras/Erk signaling pathways (Potter et al, 2002;Ma et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways

Wen

Wang

et al. 2020

Front. Mol. Neurosci.

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Neurite outgrowth is essential for brain development and the recovery of brain injury and neurodegenerative diseases. In this study, we examined the role of the neurotrophic factor MANF in regulating neurite outgrowth. We generated MANF knockout (KO) neuro2a (N2a) cell lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and demonstrated that MANF KO N2a cells failed to grow neurites in response to RA stimulation. Using MANF siRNA, this finding was confirmed in human SH-SY5Y neuronal cell line. Nevertheless, MANF overexpression by adenovirus transduction or addition of MANF into culture media facilitated the growth of longer neurites in RA-treated N2a cells. MANF deficiency resulted in inhibition of Akt, Erk, mTOR, and P70S6, and impaired protein synthesis. MANF overexpression on the other hand facilitated the growth of longer neurites by activating Akt, Erk, mTOR, and P70S6. Pharmacological blockade of Akt, Erk or mTOR eliminated the promoting effect of MANF on neurite outgrowth. These findings suggest that MANF positively regulated neurite outgrowth by activating Akt/mTOR and Erk/mTOR signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways

Wen

Wang

et al. 2020

Front. Mol. Neurosci.

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“…Signal transduction cascades: several signal transduction cascades are activated in repair Schwann cells (reviewed extensively in Nocera and Jacob, 2020 ; Stassart and Woodhoo, 2020 ), including ERK1/2 (Sheu et al, 2000 ; Harrisingh et al, 2004 ; Hausott and Klimaschewski, 2019 ), Jun N-terminal Kinase (JNK; Parkinson et al, 2008 ; Monje et al, 2010 ), and p38 MAPK (Haines et al, 2008 ; Yang et al, 2012 ) signaling. JNK activation leads to phosphorylation of Jun, induces Schwann cell proliferation, and inhibits myelination (Parkinson et al, 2004 , 2008 ; Monje et al, 2010 ).…”

Section: Molecular Regulators Of the Schwann Cell Repair Responsementioning

confidence: 99%

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

Balakrishnan

Belfiore

Chu

et al. 2021

Front. Mol. Neurosci.

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Peripheral nerve injuries arising from trauma or disease can lead to sensory and motor deficits and neuropathic pain. Despite the purported ability of the peripheral nerve to self-repair, lifelong disability is common. New molecular and cellular insights have begun to reveal why the peripheral nerve has limited repair capacity. The peripheral nerve is primarily comprised of axons and Schwann cells, the supporting glial cells that produce myelin to facilitate the rapid conduction of electrical impulses. Schwann cells are required for successful nerve regeneration; they partially “de-differentiate” in response to injury, re-initiating the expression of developmental genes that support nerve repair. However, Schwann cell dysfunction, which occurs in chronic nerve injury, disease, and aging, limits their capacity to support endogenous repair, worsening patient outcomes. Cell replacement-based therapeutic approaches using exogenous Schwann cells could be curative, but not all Schwann cells have a “repair” phenotype, defined as the ability to promote axonal growth, maintain a proliferative phenotype, and remyelinate axons. Two cell replacement strategies are being championed for peripheral nerve repair: prospective isolation of “repair” Schwann cells for autologous cell transplants, which is hampered by supply challenges, and directed differentiation of pluripotent stem cells or lineage conversion of accessible somatic cells to induced Schwann cells, with the potential of “unlimited” supply. All approaches require a solid understanding of the molecular mechanisms guiding Schwann cell development and the repair phenotype, which we review herein. Together these studies provide essential context for current efforts to design glial cell-based therapies for peripheral nerve regeneration.

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“…The assigned major role of Spry2 is the inhibition of the rat sarcoma (RAS)/extracellular signalregulated kinase (ERK) pathway (Mason et al, 2006;Hausott and Klimaschewski, 2019b), whereas PTEN has mainly been described as an inhibitor of the phosphoinositide 3-kinase (PI3K)/Akt pathway (Vazquez and Sellers, 2000;Krishnan et al, 2016). Both, the Ras/ERK and the PI3K/Akt pathway, are key players in axon growth of dorsal root ganglia (DRG) neurons (Chan et al, 2014;Hausott and Klimaschewski, 2019a).…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Knockdown of Sprouty2 and PTEN Promotes Axon Elongation of Adult Sensory Neurons

Jamsuwan

Klimaschewski

Hausott

2020

Front. Cell. Neurosci.

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Sprouty2 (Spry2) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) are both well-established regulators of receptor tyrosine kinase (RTK) signaling, and knockdown of Spry2 or PTEN enhances axon regeneration of dorsal root ganglia (DRG) neurons. The major role of Spry2 is the inhibition of the rat sarcoma RAS/extracellular signal-regulated kinase (ERK) pathway, whereas PTEN acts mainly as an inhibitor of the phosphoinositide 3-kinase (PI3K)/Akt pathway. In non-neuronal cells, Spry2 increases the expression and activity of PTEN, and PTEN enhances the amount of Spry2 by the inhibition of the microRNA-21 (miR-21) that downregulates Spry2. Applying dissociated DRG neuron cultures from wild-type (WT) or Spry2 deficient mice, we demonstrate that PTEN protein was reduced after 72 h during rapid axonal outgrowth on the laminin substrate. Furthermore, PTEN protein was decreased in DRG cultures obtained from homozygous Spry2−/− knockout mice. Vice versa, Spry2 protein was reduced by PTEN siRNA in WT and heterozygous Spry2+/− neurons. Knockdown of PTEN in DRG cultures obtained from homozygous Spry2−/− knockout mice promoted axon elongation without increasing axonal branching. Activation of Akt, but not ERK, was stronger in response to PTEN knockdown in homozygous Spry2−/− DRG neurons than in WT neurons. Together, our study confirms the important role of the signaling modulators Spry2 and PTEN in axon growth of adult DRG neurons. Both function as endogenous inhibitors of neuronal growth factor signaling and their simultaneous knockdown promotes axon elongation more efficiently than the single knockdown of each inhibitor. Furthermore, Spry2 and PTEN are reciprocally downregulated in adult DRG neuron cultures. Axon growth is influenced by multiple factors and our results demonstrate that the endogenous inhibitors of axon growth, Spry2 and PTEN, are co-regulated in adult DRG neuron cultures. Together, our data demonstrate that combined approaches may be more useful to improve nerve regeneration than targeting one single inhibitor of axon growth.

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Promotion of Peripheral Nerve Regeneration by Stimulation of the Extracellular Signal‐Regulated Kinase (ERK) Pathway

Cited by 40 publications

References 87 publications

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

Simultaneous Knockdown of Sprouty2 and PTEN Promotes Axon Elongation of Adult Sensory Neurons

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