METTL3-mediated m6A modification is required for cerebellar development

Area of Science:

• Molecular Biology
• Developmental Biology
• Neuroscience

Background:

• N6-methyladenosine (m6A) is the most abundant mRNA modification, vital for biological processes.
• Methyltransferase-like 3 (METTL3) is a key enzyme in m6A formation.
• The in vivo role of METTL3 and m6A in mammalian development is largely unknown.

Purpose of the Study:

• To investigate the in vivo function of METTL3 in mammalian nervous system development.
• To elucidate the role of m6A modification in cerebellar development.

Main Methods:

• Conditional knockout (cKO) of Mettl3 in the mouse nervous system.
• Analysis of cerebellar development and apoptosis in newborn cerebellar granule cells (CGCs).
• Assessment of RNA half-lives and splicing events upon METTL3 depletion.

Main Results:

• Mettl3 inactivation in mice led to severe brain developmental defects, specifically cerebellar hypoplasia.
• Enhanced apoptosis of CGCs in the external granular layer (EGL) was observed in Mettl3 cKO mice.
• METTL3 depletion resulted in extended RNA half-lives, aberrant splicing, and dysregulated gene expression, causing premature CGC death.

Conclusions:

• METTL3-mediated m6A RNA methylation is critical for normal mammalian cerebellum development.
• METTL3 regulates CGC survival by controlling RNA stability and splicing.
• This study highlights the essential role of m6A epitranscriptomics in neurodevelopment.