Dynamic FMR1 granule phase switch instructed by m6A modification contributes to maternal RNA decay

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• Maternal RNA degradation is crucial for embryogenesis, regulated by RNA-binding proteins.
• Fragile X mental-retardation protein (FMR1) forms ribonucleoprotein (RNP) complexes controlling biological processes, including embryogenesis.
• Mechanisms of FMR1 mRNA recognition and RNP granule dynamics in RNA regulation are not fully understood.

Purpose of the Study:

• To elucidate how FMR1 recognizes target mRNAs.
• To investigate the role of FMR1-RNP granule assembly/disassembly in regulating FMR1-associated mRNAs.
• To understand the contribution of FMR1 to maternal RNA degradation and embryogenesis.

Main Methods:

• Investigated FMR1 binding preferences to specific mRNA motifs.
• Analyzed the structural basis of FMR1-mRNA interaction using its KH2 domain.
• Observed FMR1-RNP granule dynamics in response to mRNA binding and degradation.

Main Results:

• Drosophila FMR1 preferentially binds m6A-marked "AGACU" motifs in mRNAs with high affinity.
• High-affinity binding induces FMR1-RNP granule condensation, recruiting additional mRNAs.
• Maternal mRNA degradation leads to RNP granule de-condensation, enabling normal embryogenesis.

Conclusions:

• Sequence-specific mRNAs trigger dynamic phase-switching of FMR1-RNP granules, facilitating maternal mRNA decay.
• This regulated RNP granule mechanism is critical for maternal RNA processing and embryonic development.
• The findings suggest a general principle for how RNP granules control RNA processing and development.