N⁶-methyladenosine (m⁶A) is a reversible modification in mRNA and has been shown to regulate processing, translation and decay of mRNA. However, the roles of m⁶A modification in neuronal development are still not known. Here, we found that the m⁶A eraser FTO is enriched in axons and can be locally translated. Axon-specific inhibition of FTO by rhein, or compartmentalized siRNA knockdown of Fto in axons led to increases of m⁶A levels. GAP-43 mRNA is modified by m⁶A and is a substrate of FTO in axons. Loss-of-function of this non-nuclear pool of FTO resulted in increased m⁶A modification and decreased local translation of axonal GAP-43 mRNA, which eventually repressed axon elongation. Mutation of a predicted m⁶A site in GAP-43 mRNA eliminated its m⁶A modification and exempted regulation of its local translation by axonal FTO. This work showed an example of dynamic internal m⁶A demethylation of non-nuclear localized mRNA by the demethylase FTO. Regulation of m⁶A modification of axonal mRNA by axonal FTO might be a general mechanism to control their local translation in neuronal development.

中文翻译：

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动态 m6A 修饰调节轴突中 mRNA 的局部翻译

N ⁶ -甲基腺苷 (m ⁶ A) 是 mRNA 中的可逆修饰，并已显示调节 mRNA 的加工、翻译和衰变。然而，m ⁶ A 修饰在神经元发育中的作用仍然未知。在这里，我们发现 m ⁶ A 橡皮擦 FTO 富含轴突，可以进行局部翻译。通过大黄酸，或区室化的siRNA敲低的FTO特定轴突抑制F至在导致米的增加轴突⁶ A水平。GAP-43 mRNA 被 m ⁶ A修饰，是轴突中 FTO 的底物。这种非核 FTO 池的功能丧失导致 m ⁶增加轴突GAP-43 mRNA的修饰和局部翻译减少，最终抑制轴突伸长。GAP-43 mRNA 中预测的 m ⁶ A 位点的突变消除了其 m ⁶ A 修饰并免除了轴突 FTO 对其局部翻译的调节。这项工作展示了通过去甲基化酶 FTO 对非核定位 mRNA进行动态内部 m ⁶ A 去甲基化的一个例子。m ⁶的调节 轴突 FTO 对轴突 mRNA 的修饰可能是控制其在神经元发育中的局部翻译的一般机制。