The Bao Lan group revealed the development and mechanism of m6A-modified long-encoded RNA regulating neuronal development

On November 22, the international academic journal Cell Reports published online the latest research progress of Bao Lan's research group of the Center for Excellence in Molecular Cell Science (Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences A-modified lincRNA Dubr is required for neuronal development by stabilizing YTHDF1/3 and facilitating mRNA translation”
。 The study revealed the molecular mechanism
by which^m6Amodification of long non-coding RNA (lncRNA) Dubr regulates axon growth and neuronal migration by stabilizing the YTHDF1/3 complex and its mediated mRNA translation.

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 synthesize new proteins through local dynamic translation of mRNA, which is involved in regulating neuronal development and the establishment
of neural networks 。 Previous research work in the research group found that microRNAs (miRNAs) are enriched in axons of primary sensory neurons, while participating in axon extension by regulating local translation in axons (Wang et al.
, Cell Reports, 2015; Wang & Bao, Journal of Molecular Cell Biology, 2017）
。 Recent studies have found that axon-enriched lncRNA ALAE regulates axon local translation and participation in axon growth by competing for the RNA-binding protein KHSRP and interacting with Gap43 mRNA (Wei et al.
, Cell Reports, 2021).

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

RNA methylation modifications are the most prevalent and enriched of hundreds of RNA
modifications.
N6-methyladenosine (^m6A) is the most abundant dynamic modification and is involved in important cell biological processes
such as RNA metabolism, splicing, translation, nucleation, and transport.
Previous studies have shown that^m6Amethylation modification is highly enriched in mammalian brains and plays an important role
in early neuronal differentiation, growth, and learning and memory.
Although recent studies suggest that lncRNAs regulate neuronal axon development (Wei et al.
, Cell Reports, 2021), little is known about the presence or absence of m6A modifications and the function and mechanism of^m6Amodifications involved in lncRNA neurodevelopment
.

In this study,^m6A-CLIP data and different tissue developmental sequencing data in mouse dorsal root ganglion (DRG) tissues were first integrated and analyzed, and it was found that lncRNA Dubr was highly modified by^m6Aand was highly expressed
in early nervous system development.
Using in vitro DRG tissue culture, neuronal microfluidic chamber separation culture and embryonic electrotransfer, 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^m6Amodification site could not restore the developmental defects
of neurons.
Further studies found that Dubr interacts with m6A reading proteins YTHDF1 and YTHDF3 via the m6A modification site, while knocking down the^m6Asite of Dubror mutant Dubr 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 all regulate the mRNA translation of Calmodulin and Tau, molecules related to neuronal development, and Dubr promotes the stability of YTHDF1/3 protein complex through^m6Amethylation to maintain the mRNA translation of Calmodulin and Tau and promote axon growth of sensory neurons and correct migration
of cortical neurons.

In summary, this study reveals the function of^m6Adynamic 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^m6Adynamic 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, is the first author of this paper, and Professor Bao Lan and Professor Wang Bin of Guangdong Institute of Intelligent Science and Technology are co-corresponding authors
.
This work is strongly supported
by Professor Yang Li from the Institute of Biomedical Sciences of Fudan University, Professor Zhang Xu from the Shanghai Advanced Research Institute of the Chinese Academy of Sciences, and Professor Jiang Xingyu from Southern University of Science and Technology.
This work was funded
by the National Foundation of China and the Guangdong High-level Innovation Research Institute.

Article link:

m6A-modified lncRNA Dubr is involved in regulating neuronal development by stabilizing the YTHDF1/3 complex and promoting mRNA translation