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Dynamic m6A modification regulates local translation of mRNA in axons

Jun Yu1,2, Mengxian Chen1, Haijiao Huang1

  • 1Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.

Nucleic Acids Research
|November 30, 2017
PubMed

Insights

The study reveals that the FTO enzyme regulates N6-methyladenosine (m6A) RNA modifications within neuronal axons, impacting the translation of GAP-43 mRNA and controlling axon growth.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Epigenetics

Background:

  • N6-methyladenosine (m6A) is a crucial mRNA modification influencing RNA processing, translation, and decay.
  • The specific roles of m6A modifications in neuronal development remain largely unexplored.
  • The m6A demethylase FTO (Fat mass and obesity-associated protein) is implicated in various biological processes.

Purpose of the Study:

  • To investigate the function of the m6A eraser FTO in neuronal development, particularly within axons.
  • To determine if m6A modification plays a role in regulating axonal mRNA translation and neuronal growth.

Main Methods:

  • Investigated FTO localization and local translation in axons.
  • Utilized axon-specific inhibition of FTO with rhein and compartmentalized siRNA knockdown of Fto.
  • Analyzed m6A levels, GAP-43 mRNA modification, and its local translation in axons.
  • Employed site-directed mutagenesis to assess the impact of m6A modification on GAP-43 mRNA.

Main Results:

  • FTO is enriched in axons and can be locally translated, acting as an m6A 'eraser'.
  • Inhibition or knockdown of axonal FTO increased m6A levels and decreased local translation of axonal GAP-43 mRNA.
  • This led to repressed axon elongation, indicating FTO's critical role in regulating axonal mRNA.
  • Mutation of the m6A site in GAP-43 mRNA abolished m6A modification and FTO-mediated translational regulation.

Conclusions:

  • Demonstrates dynamic, non-nuclear m6A demethylation of localized axonal mRNA by FTO.
  • Axonal FTO regulates local translation of axonal mRNA, such as GAP-43, impacting neuronal development.
  • This highlights a potential general mechanism for controlling mRNA translation in axons via m6A modification.

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