Much like a courier reading an address on a package, neurons must deliver RNA to the precise locations where it is needed. A KAIST research team has discovered how a small chemical modification on RNA acts as a “delivery tag,” helping selected RNAs travel to distant regions of neurons.

The findings provide a basis for investigating RNA “delivery errors” in brain disorders—cases in which RNA is produced normally but fails to reach its intended destination—and may ultimately inform the development of new therapeutic strategies.

KAIST (President Choongsik Bae) announced on September 14 that a research team led by Professor Ki-Jun Yoon of the Department of Biological Sciences has identified a mechanism through which N6-methyladenosine, or m6A, facilitates the transport of specific RNAs to distal axons, the long, cable-like projections of neurons.

Unlike most other cells, neurons have long, highly branched extensions. Axons transmit signals to other neurons, while dendrites receive incoming signals. For the brain to develop and function normally, these structures must grow properly and form appropriate connections.

Because neurons can extend over considerable distances, RNA produced in the cell body may be needed far away, including at the growing tip of an axon. Neurons must therefore identify particular RNAs among thousands of candidates and transport them to the correct subcellular locations.

Just as producing a package does not complete its delivery—the package must also reach the correct address—producing RNA is only part of the process. RNA must arrive at the right place at the right time. However, the mechanisms through which neurons select and transport RNAs over long distances have remained incompletely understood.

The research team found that m6A, a small chemical modification added to RNA, plays an important role in this process. m6A is a modification of adenosine, one of the building blocks of RNA, and is known to influence several aspects of RNA metabolism, including stability and translation. The new study shows that m6A can also function as a molecular “delivery tag” that promotes the transport of specific RNAs to distal regions of neurons.

The researchers first examined mice in which Mettl14, a component of the enzyme complex that installs m6A on RNA, was deleted from developing neurons. In the absence of normal m6A modification, the neurons exhibited impaired axon projection and neurite development. These findings confirmed that m6A plays an important role in the early development of neurons.

The team then used a high-resolution technique known as m6A-SAC-seq to map the precise locations of m6A modifications in RNA from the developing mouse brain at single-nucleotide resolution. The resulting map revealed that RNAs associated with axon development and synapse organization were among those marked by m6A.

The researchers also identified how this “delivery tag” is recognized and connected to the cellular transport machinery. They found that YTHDF2, a protein that recognizes m6A-modified RNA, works with the RNA-binding protein FMRP and the motor protein KIF5C to facilitate the transport of RNA along neuronal processes.

In the delivery analogy, m6A serves as the tag attached to the RNA, YTHDF2 reads the tag, and FMRP and KIF5C help connect the RNA to the cellular machinery that carries it toward its destination.

YTHDF2 has previously been studied primarily for its role in promoting the degradation of RNA that is no longer needed. This study reveals an additional function: in developing neurons, YTHDF2 also helps transport specific RNAs to distal locations rather than simply directing them toward degradation.

The findings offer a new perspective on the study of brain disorders. Research has traditionally focused on whether RNA is produced and maintained correctly. The new results suggest that researchers should also consider whether normally produced RNA is delivered to the correct location within a neuron.

In other words, neurological dysfunction may potentially arise not only from defects in RNA itself, but also from problems with the molecular tags or transport machinery that determine where the RNA travels.

Future studies could investigate whether such RNA delivery errors occur in neurodevelopmental or neurodegenerative disorders and whether they contribute to neuronal dysfunction or disease onset. If such links are established, the findings could eventually support the development of therapeutic approaches that regulate RNA transport and restore the delivery of specific RNAs to their intended locations.

The high-resolution m6A map of the developing nervous system generated in this study may also serve as a valuable resource for examining how RNA modification and intracellular transport change during brain aging and neurodegenerative disease.

“Our study shows that a small chemical modification on RNA does more than regulate RNA stability—it also plays an important role in delivering specific RNAs to the locations where they are needed within neurons,” said Professor Yoon. “We hope these findings will provide a foundation for understanding why RNA may fail to reach its intended destination in brain disorders and for exploring new therapeutic possibilities.”

Bonsang Koo, Dr. Ajeet Kumar, and Huiseon Hwang of the KAIST Department of Biological Sciences contributed equally to the study as co-first authors. The paper was published in Nature Communications on July 30.

Paper title: “The m⁶A reader YTHDF2 regulates mRNA transport and axon outgrowth in developing neurons”
DOI: 10.1038/s41467-026-76161-8
Author information: Co-first authors (Bonsang Koo, Ajeet Kumar, Huiseon Hwang); Contributing authors (Minyeong Park, Sung-Min Lee, Ki-Heon Lee, Ji-Hoon Moon, Jaewon Yang, Chan-Woo Park, Saebom Lee, Hee-Jung Jo, Woo-il Kim, Eunji Cho, Hagyeong Lee, Chang-Won Lee, Jae-Sung Woo, Jong Hyuk Yoon, Yoon Ki Kim); Corresponding author (Ki-Jun Yoon)
This work was supported by National Research Foundation of Korea (NRF) grants (2020M3A9E403967022, RS-2024-00332454, RS-2024-00440778, and RS-2026-25488918 to K.-J.Y.) funded by the Korean Ministry of Science and ICT, and Future Planning (MSIP), the POSCOScience Fellowship from the POSCO TJ Park Foundation (to K.-J.Y.), the Young Investigator Grant from the Suh Kyungbae Foundation (to K.-J.Y.), the Korea Brain Research Institute (KBRI) Basic Research Program through the Korea Brain Research Institute, funded by the Ministry of Science and ICT (MSIT) (24-BR-02-03 to J.H.Y).