Cell sub-journal: Bao Lan's team reveals the molecular mechanism by which m6A-modified lncRNA regulates neurodevelopment

Neurons are a class of highly specialized cells with complex dendrites and axons
.
The mRNA in the neuronal soma can be transported to dendrites and axons, and new proteins can be synthesized through local dynamic translation of mRNA to regulate neuronal development and the correct establishment of
neural networks.
The previous research work of Bao Lan's group found that miRNAs are enriched in axons of primary sensory neurons, and at the same time participate in axon extension
by regulating local translation in axons.
Recent studies have found that axon-enriched lncRNA ALAE regulates axonal local translation and axon growth
by competing for the RNA-binding protein KHSRP and interacting with Gap43 mRNA.

The above studies show that non-coding RNAs play an important regulatory role
in the development of neurons.

On November 22, 2022, the research group of Bao Lan of the Center for Excellence in Molecular Cell Science (Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences published an online report in the journal Cell Reports entitled: m6A-modified lincRNA Dubr is required for neuronal development by stabilizing YTHDF1/3 and facilitating mRNA Translation's research paper
.

This study reveals the molecular mechanism
by which m6A modification of Dubr regulates neuronal axon growth and migration by stabilizing the YTHDF1/3 complex and its mediated mRNA translation.

RNA methylation modifications are the most prevalent and enriched of hundreds of RNA
modifications.
N6-methyladenosine (m6A) is the most abundant dynamic modification involved in important cell biological processes
such as RNA metabolism, splicing, translation, nucleation and transport.
Previous studies have shown that m6A methylation modification is highly enriched in mammalian brains and plays an important role
in early neuronal development and learning and memory.

Recent studies suggest that lncRNA regulates neuronal axon development, but the presence or absence of m6A modification in lncRNA and the function and mechanism of m6A modification in lncRNA participation in neuronal development are poorly
understood.

In this study, m6A-CLIP and different tissue development sequencing data in mouse dorsal root ganglion (DRG) tissues were first integrated, and it was found that lncRNA Dubr was highly modified by m6A and highly expressed
in the early stage of nervous system development.

Using in vitro DRG tissue culture, neuronal microfluidic chamber separation culture and embryonic electroporation, it was found that knocking down Dubr could hinder the axon growth of DRG neurons and lead to cortical neuron migration and axonal projection defects, while mutation of Dubr's m6A modification site could not restore the developmental defects
of neurons.

Further studies found that Dubr interacts with m6A reading proteins YTHDF1 and YTHDF3 through m6A modification sites, while knocking down Dubr or Dubr mutant m6A sites can accelerate the entry of YTHDF1 and YTHDF3 proteins into the proteasome-dependent degradation pathway, ultimately leading to a significant decrease
in protein levels 。 At the same time, Dubr, YTHDF1 and YTHDF3 can regulate the mRNA translation of the genes Calmodulin and Tau associated with neuronal development, and Dubr promotes the stability of YTHDF1/3 protein complex through m6A methylation to maintain the mRNA translation of Calmodulin and Tau and promote axon growth of sensory neurons and correct migration
of cortical neurons.

m6A-modified lncRNA Dubr regulates neuronal development by stabilizing the YTHDF1/3 complex and promoting mRNA translation

In summary, this study reveals the function of m6A dynamic modification of lncRNA in neuronal development to regulate mRNA translation by stabilizing
RNA-binding proteins.
This study deepens the understanding of the function and mechanism of m6A dynamic modification on noncoding RNA, and also provides a new perspective
for exploring the complex regulatory mechanism of nervous system development.

Huang Jiansong, a doctoral student in the Bao Lan Research Group of the Center of Excellence for Molecular Cells of the Chinese Academy of Sciences, is the first author of the paper, and Professor Bao Lan and Professor Wang Bin of Guangdong Institute of Intelligent Science and Technology are co-corresponding authors
of the paper.
This work was strongly supported
by Prof.
Li Yang from the Institute of Biomedical Sciences of Fudan University, Prof.
Xu Zhang from the Shanghai Advanced Research Institute of the Chinese Academy of Sciences, and Prof.
Xingyu Jiang from Southern University of Science and Technology.
The work was funded
by the National Foundation of China and the Guangdong High-level Innovation Research Institute.

Paper Link:

https://doi.
org/10.
1016/j.
celrep.
2022.
111693