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Frontiers in molecular neuroscience
2020;13 560020.

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

Wen Wen, Yongchao Wang, Hui Li, Hong Xu, Mei Xu, Jacqueline A Frank, Murong Ma, Jia Luo
Author Information
  1. Wen Wen: Department of Pathology, University of Iowa, Iowa City, IA, United States.
  2. Yongchao Wang: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States.
  3. Hui Li: Department of Pathology, University of Iowa, Iowa City, IA, United States.
  4. Hong Xu: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States.
  5. Mei Xu: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States.
  6. Jacqueline A Frank: Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, United States.
  7. Murong Ma: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States.
  8. Jia Luo: Department of Pathology, University of Iowa, Iowa City, IA, United States.
PMID: 33071755 DOI: 10.3389/fnmol.2020.560020

Abstract

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.

Keywords

Akt/mTOR Erk/mTOR MANF neurite outgrowth neuronal differentiation neurotrophic factor protein synthesis

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Grants

  1. I01 BX001721/BLRD VA
  2. R01 AA015407/NIAAA NIH HHS
  3. R01 AA017226/NIAAA NIH HHS
Journal Article
Article has an altmetric score of 2

Word Cloud

Created with Highcharts 10.0.0MANFoutgrowthneuriteN2aneuritesAktErkmTORAkt/mTORErk/mTORNeuritebrainneurotrophicfactorKOcellcellsneuronaloverexpressionfacilitatedgrowthlongerP70S6proteinsynthesisactivatingessentialdevelopmentrecoveryinjuryneurodegenerativediseasesstudyexaminedroleregulatinggeneratedknockoutneuro2alinesusingclusteredregularlyinterspacedshortpalindromicrepeatsCRISPR/Cas9demonstratedfailedgrowresponseRAstimulationUsingsiRNAfindingconfirmedhumanSH-SY5YlineNeverthelessadenovirustransductionadditionculturemediaRA-treateddeficiencyresultedinhibitionimpairedhandPharmacologicalblockadeeliminatedpromotingeffectfindingssuggestpositivelyregulatedsignalingpathwaysMesencephalicAstrocyte-DerivedNeurotrophicFactorRegulatesOutgrowthActivationSignalingPathwaysdifferentiation

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