On November 23, Associate Professor Sheng-Jian Ji’s group from the Department of Biology published a paper entitled “Dynamic m6A modification regulates local translation of mRNA in axons” in Nucleic Acids Research. This study reveals a new mechanism that m6A modification can regulate axon growth by controlling mRNA local translation in axons.

N6-methyladenosine (m6A) has been identified as the most prevalent internal modification in mRNA. This modification is a dynamic process which can influence mRNA splicing, localization, translation, decay and so on. m6A was first discovered in 1970s, however, this modification draws extensive researchers’ attention only in recent years and becomes a research hotspot gradually. Accumulating studies have shown that m6A modification regulates multiple biological processes, including pluripotency of embryonic stem cells, somatic cell reprogramming, UV induced DNA damage response, spermatogenesis, haematopoietic stem and progenitor cell specification, cortical neurogenesis and so on. However, whether m6A modification can mediate neural development is still largely unknown.

The methylation process of m6A modification is catalyzed by a methyltransferase complex including METTL3 and METTL14, whereas the demethylation is mediated by FTO or ALKBH5. Previous studies have shown that FTO mainly concentrates in nucleus. However, Prof. Ji’s group, for the first time, found that FTO not only expressed in nucleus, but also surprisingly expressed in axons of mouse dorsal root ganglion (DRG) neurons. Interestingly, they also discovered that this axonal FTO was derived from local translation as FTO mRNA was detected in axons. Axonal specific inhibition of FTO (by rhein treatment) or specific knockdown of Fto can significantly increase the level of m6A on mRNA and remarkably inhibited axon growth.

To further investigate the underlying mechanism, Prof. Ji’s group found that both specific inhibition of FTO and knockdown of Fto significantly reduced the level of local translation of GAP-43 mRNA. Anti-m6A pull down experiments verified that FTO regulates local translation of GAP-43mRNA by changing the m6A level of GAP-43 mRNA. In neurons overexpressing wildtype GAP-43, loss-of-function of FTO can dramatically decrease local translation of GAP-43 mRNA and suppress axon growth, while in neurons overexpressing GAP-43 with its m6A site mutated, loss-of-function of FTO had no impact on local translation of GAP-43 and axon growth. Therefore, this study showed that FTO can regulate the m6A level of GAP-43 mRNA which further affect local translation of GAP-43 mRNA and eventually influence axon growth.

SUSTech-HKU Joint PhD Program student Jun Yu, SUSTech undergraduate student Mengxian Chen and research assistant Haijiao Huang are the co-first authors of this Paper. As co-authors, SUSTech Prof. Jaewon Park’s group supplied the microfluidic chamber masters. Prof. Ji is the corresponding author. This work was supported by startup funds from SUSTech and Peacock Plan of Shenzhen, Natural Science Fund of Guangdong Province, Science and Technology Innovation Commission of Shenzhen Municipal Government.

Link to the paper: https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkx1182/4653533