TDP-43 Regulates Coupled Dendritic mRNA Transport-Translation Processes in Co-operation with FMRP and Staufen1

Abstract

Summary: Tightly regulated transport of messenger ribonucleoprotein (mRNP) granules to diverse locations of dendrites and axons is essential for appropriately timed protein synthesis within distinct sub-neuronal compartments. Perturbations of this regulation lead to various neurological disorders. Using imaging and molecular approaches, we demonstrate how TDP-43 co-operates with two other RNA-binding proteins, FMRP and Staufen1, to regulate the anterograde and retrograde transport, respectively, of Rac1 mRNPs in mouse neuronal dendrites. We also analyze the mechanisms by which TDP-43 mediates coupled mRNA transport-translation processes in dendritic sub-compartments by following in real-time the co-movement of RNA and endogenous fluorescence-tagged protein in neurons and by simultaneous examination of transport/translation dynamics by using an RNA biosensor. This study establishes the pivotal roles of TDP-43 in transporting mRNP granules in dendrites, inhibiting translation inside those granules, and reactivating it once the granules reach the dendritic spines. : Chu et al. explore mechanisms of TDP-43-mediated dendritic mRNA transport, combining molecular approaches, real-time imaging, and an RNA biosensor. Analysis of the kinetics and dynamics of coupled transport-translation processes of Rac1 mRNA in neuronal dendrites demonstrates that TDP-43 regulates these processes in cooperation with FMRP and Staufen1 in different subcompartments. Keywords: TDP-43, FMRP, Kinesin1, hippocampal neuron dendrites, RNA granule transport-translation, live-cell imaging, RNA FISH, fluorescence tagging by genome editing, TRICK reporter RNA