FMRP Enhances the Translation of 4EBP2 mRNA During Neuronal Differentiation: A New Perspective of FMRP Function in Fragile X Syndrome

Abstract

Neurons, distinguished by unique features such as neurites (axon and dendrite) and synapses, necessitate precise translation control to orchestrate the proliferation and differentiation. The identification of translational machinery and mRNA at the neurite's periphery supports the hypothesis that spatiotemporally regulated mRNA translation may influence neurite function or developmental stages in differentiating neurons. The translation of mRNAs functionally associated with neurons remain translationally repressed until they reach their destination—an endeavor facilitated by RNA-binding proteins, with Fragile X Messenger Ribonucleoprotein 1 (FMRP) standing out as a prominent example of a repressive RNA-binding protein. FMRP is a multifunctional protein encoded by the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1). The inactivation of the FMR1 gene results in fragile X syndrome (FXS), a serious neurodevelopmental disorder. FMRP deficiency causes abnormal neurite outgrowth, which is likely to lead to abnormal learning and memory capabilities. However, the mechanism of FMRP in modulating neuronal development remains unknown. We found that FMRP enhances the translation of 4EBP2, a neuron-specific form of 4EBPs that inactivates eIF4E by inhibiting the interaction between eIF4E and eIF4G. Depletion of 4EBP2 results in abnormal neurite outgrowth. Moreover, the impairment of neurite outgrowth upon FMRP depletion was overcome by the ectopic expression of 4EBP2. These results suggest that FMRP controls neuronal development by enhancing 4EBP2 expression at the translational level. In addition, treatment with 4EGI-1, a chemical that blocks eIF4E activity, restored neurite length in FMRP-depleted and 4EBP2-depleted cells. In conclusion, we discovered that 4EBP2 functions as a key downstream regulator of FMRP activity in neuronal development and that FMRP represses eIF4E activity by enhancing 4EBP2 translation. Finally, I am in the process of developing a technique utilizing fluorescent microscopy to visualize the translation initiation process. The objective is to provide evidence supporting the translation is initiated through an 'RNA looping’ model rather than a 'scanning' process.