Sun Yat-sen University, Zhongshan Ophthalmic Center Guangzhou, Guangdong, China (People's Republic)
Abstract: Retinal ganglion cells (RGCs) are the key neurons responsible for transmitting visual information to the brain, and their degeneration in retinal diseases such as glaucoma leads to severe vision loss. N6-methyladenosine (m6A) modification plays a crucial role in gene expression and cellular functions in eukaryotes, including nervous system development. However, the specific functions of m6A modification in RGC remain unclear. Our previous research has demonstrated that the transcription factors Ascl1, Brn3b, and Isl1 can efficiently induce fibroblasts into RGC-like neurons (iRGCs), providing a robust experimental platform for studying RGC development and physiology. Using this iRGC model, we investigated the functions of Mettl3, the key catalytic component of the m6A-writer complex, in RGC. Our results showed that METTL3 knockdown significantly impaired axon growth and reduced iRGC induction efficiency, while METTL3 overexpression significantly promoted iRGC axon growth. RNA sequencing and m6A sequencing revealed downstream target genes regulated by METTL3 and its mediated m6A modification, which play complex roles in RGC axon growth. Thus our study demonstrated that METTL3-mediated m6A modification positively regulates axonogenesis and neurogenesis during RGC reprogramming. Our findings deepen our understanding of the molecular networks governing RGC axon development and regeneration and identify new targets for potential therapies for RGC degenerative diseases.
Funding Source: the National Natural Science Foundation of China (32470848).
