p70 S6 Kinase 1-dependent alterations in cortical mRNA translation in fragile X syndrome mice

Fragile X syndrome (FXS) is caused by loss of the fragile X mental retardation protein (FMRP). The mechanism by which FMRP regulates messenger RNA (mRNA) translation remains disputed. We observed reduced ribosome footprint abundance in the majority of differentially translated genes in cortices of FXS mice, which was correlated with an increased rate of ribosome translocation that was normalized by inhibition of p70 S6 Kinase 1 (S6K1). We also show that alterations in translation efficiencies across mRNAs in FXS mouse cortices exhibit a positive to negative gradation with coding sequence length, which is prevented by the genetic reduction of S6K1. Our findings reveal the identity of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS. Examination of genome-wide translational state in wild-type, Fmr1-deficient, Rps6kb1-deficient, and double knockout (Fmr1 and Rps6kb1 deficient) mouse cortices via next-generation sequencing-based profiling of transcription and translation.