FMRP prevents Me31B/DDX6-associated repression of long neurodevelopmental mRNAs

Abstract

Long, dosage-sensitive mRNAs encoding neurodevelopmental regulators are selectively dependent on fragile X messenger ribonucleoprotein (FMRP) for efficient translation across animal systems, but the mechanism underlying this length-dependent requirement remains unclear. Here, we show that FMRP maintains translation of long target mRNAs by preventing their inappropriate sequestration into a Me31B/DDX6-dependent P-body repression pathway. In Drosophila oocytes, loss of FMRP caused target mRNAs, but not bulk polyadenylated RNA, to accumulate in Me31B-marked P-bodies. Improved individual-nucleotide resolution crosslinking and immunoprecipitation (iiCLIP) revealed that FMRP and Me31B co-occupy many long coding sequences, suggesting that FMRP targets are intrinsically vulnerable to repressive Me31B-associated machinery. A screen targeting ∼120 candidate genes, followed by proteomic analysis, identified an FMRP-associated ribonucleoprotein (RNP) assembly containing the stress granule-linked proteins Rin/G3BP, Lig/UBAP2L, and Capr/Caprin1. These factors supported translation or localization of distinct FMRP target subsets. Finally, inhibition of Me31B-dependent repressive complex assembly restored translation of the majority of FMRP targets in FMRP-deficient oocytes, supporting a model in which translational failure results from excessive repression. Together, these findings reveal a cytoplasmic RNP assembly that safeguards mRNAs by antagonizing promiscuous P-body repression and provide a mechanistic explanation for the selective vulnerability of long neurodevelopmental transcripts to FMRP loss.