TDP-43 Regulates Coupled Dendritic mRNA Transport-Translation Processes in Co-Operation with FMRP and Staufen1: A Mechanistic View
63 Pages Posted: 30 Oct 2018 Sneak Peek Status: Under ReviewMore...
Tightly regulated transport of mRNAs in the form of mRNP granules to diverse locations of the dendrites and axons is essential for timed protein synthesis within distinct sub-neuronal compartments. Perturbations in this regulation lead to neurodevelopmental disorders and/or neurodegenerative diseases. With different imaging and molecular approaches including CRISPR/Cas9 mediated gene-tagging and the use of mRNA beacon, we demonstrate the co-operative actions of TDP-43 with FMRP in recruiting the microtubule motor protein kinesin1 to regulate the anterograde transport of endogenous Rac1 mRNPs, and with Staufen1 to regulate their retrograde transport in mouse neuronal dendrites. Using a fluorescence reporter RNA-based biosensor, we also follow in real time the TDP-43-meadiated fate of un-translated RNA granules to become translated during their transport to the different dendritic sub-compartments including the spine areas. This study establishes the pivotal role and the underlying mechanisms of TDP-43 in the coupling of transport and translation processes of dendritic mRNAs.
Keywords: TDP-43; FMRP; Kinesin1; Staufen1; Dynein1; Live-cell FISH study; Genome editing; Comovement; Over-expression system; TRICK reporter RNA
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