Phosphoregulated FMRP phase separation models activity-dependent translation through bidirectional control of mRNA granule formation

Significance Activity-dependent translation, the reversible activation of translation in response to synaptic activity, is important for synaptic plasticity and long-term memory formation. How synaptic activity triggers translation of silenced mRNAs within neuronal granules, which are membraneless RNA–protein assemblies, is not clear. We show that the C-terminal region of the Fragile X Mental Retardation Protein (FMRP), an abundant neuronal granule protein, phase separates in vitro with RNA and that its phase separation is fine-tuned by posttranslational modifications controlled in neurons by synaptic activity. We observe that phase separation is correlated with translation inhibition in vitro, providing a conceptual framework to unify FMRP’s diverse roles. Experimental and bioinformatic data suggest that phase separation may be a general mechanism linked to activity-dependent translation.