[초청강연] Deciphering the neural epitranscriptome: versatile roles of m6A modification during neurodevelopment

Deciphering the Neural Epitranscriptome: The Roles of m 6 A RNA Modification in Neurodevelopment

Ajeet Kumar, Bonsang Koo, Jewon Yang, Ki-Jun Yoon
Department of Biological Sciences, KAIST, Daejeon 34141, Korea

Proper development of the nervous system is critical for its function, and deficits in neural development have
been implicated in many brain disorders. Recent discoveries of widespread mRNA chemical modifications raise
the question of whether this mechanism plays post-transcriptional regulatory role in development and function
of the brain. N6-methyladenosine (m 6 A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most
prevalent internal mRNA modification that controls various aspects of mRNA metabolism, including stability,
translation, splicing, and localization. Neurons are distinctly polarized cells where mRNA can be transported
and localized in distal structures like axons and dendrites. However, how m 6 A modification influences such
RNA localization in developing neurons has not been understood well. Here, we showed that Mettl14 deletion
in postmitotic neurons resulted in diminished m 6 A content and impaired axonal projection during corticogenesis.
RNA-seq analysis and single molecule in situ hybridization experiments revealed subsets of mRNA targets were
mis-localized in the neurites of postmitotic neurons with m 6 A loss-of-function. Further, we identified YTHDF2
is the reader protein responsible for mRNA transportation and localization in interhemispheric callosal axons in
the developing brain. Our study will enlighten the epitranscriptomic mechanism to regulate axon projection and
guidance in during mammalian cortical neurogenesis.