FYN, a Novel Target of Fragile X Mental Retardation Protein, Potentially Underlies ERK1/2 Hyperactivation in Fragile X Syndrome.

BACKGROUND: Fragile X syndrome (FXS), the most common inherited form of intellectual disability and the leading monogenic cause of autism, results from the loss of the fragile X mental retardation protein (FMRP). Dysregulated translation of FMRP target mRNAs is believed to underlie the aberrant synaptic plasticity observed in FXS. Identification of these targets is critical for elucidating disease mechanisms and developing therapeutic strategies. METHODS: We confirmed the interaction between FMRP and FYN mRNA by RNA immunoprecipitation in HEK293 and SH-SY5Y cells and assessed FYN translational regulation via polyribosome profiling in FXS and control lymphoblastoid cells. The role of FYN in ERK hyperactivation was examined in FXS lymphoblastoid cells, FMR1-knockdown SH-SY5Y cells, and dfmr1 mutant flies. Additionally, we tested whether reducing or inhibiting Src64B, a Drosophila Src family kinase with homology to human FYN, could rescue neural and behavioral defects in dfmr1 mutants. RESULTS: FMRP bound to FYN mRNA and suppressed its translation without affecting mRNA stability. Phosphorylated ERK1/2 levels were markedly elevated in FXS lymphoblastoid cells, and this hyperactivation was largely reversed by either the Src family kinase inhibitor PP2 or siRNA-mediated FYN knockdown, supporting an important role for FYN in ERK1/2 dysregulation. Similar changes were observed in FMR1-knockdown SH-SY5Y cells, with increased FYN expression and ERK1/2 phosphorylation, and PP2 treatment attenuated the abnormal ERK1/2 phosphorylation. Furthermore, genetic or pharmacological suppression of Src64B restored ERK signaling and rescued mushroom body defects and memory deficits in dfmr1 mutants. CONCLUSIONS: This study identifies FYN as a novel translational target of FMRP and suggests that its upregulation may contribute to hyperactivation of ERK1/2 signaling in FXS.