2023 Fiscal Year Annual Research Report
The role of RNA methylation in cytoskeleton regulation during axon development
| Project/Area Number |
22KF0399
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| Allocation Type | Multi-year Fund |
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
王 丹 国立研究開発法人理化学研究所, 生命機能科学研究センター, チームリーダー (50615482)
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| Co-Investigator(Kenkyū-buntansha) |
BROIX LOIC 国立研究開発法人理化学研究所, 生命機能科学研究センター, 外国人特別研究員
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| Project Period (FY) |
2023-03-08 – 2024-03-31
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| Keywords | microtubule / N6-methyl-adenosine / cytoskeleton / YTHDF1 / beta actin / axon development |
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| Outline of Annual Research Achievements |
Subcellular mRNA localization and local translation are crucial for spatially regulated gene expression in neurons. However, the precise mechanisms regulating the selective transport and translation of mRNAs contributing to processes such as axonal growth and branching are only partially understood. Here, we present evidence of N6-methyladenosine (m6A)-mediated translational control of the RNA-binding protein, APC, influencing cytoskeletal dynamics at the growth cone. Our findings demonstrate that m6A modifications occur on Apc mRNA, with subsequent recognition and binding by YTHDF1 to promote APC translation in neuronal somata. Moreover, we observe that disrupting the m6A pathway interferes with the transport and local translation of β-actin mRNA in the axon and growth cone, a deficit that can be rescued by the exogenous expression of APC protein in cultured neurons. Furthermore, we show that YTHDF1 is required for the development of axons in callosal projection neurons in vivo during cortical development. Our findings suggest a novel mechanism involving m6A-mediated regulation of APC protein translation, linking epitranscriptomics to axonal mRNA targeting, cytoskeletal dynamics, and axon development.
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