KHSRP-mediated Decay of Axonally Localized Prenyl-Cdc42 mRNA Slows Nerve Regeneration

The small GTPase CDC42 promotes axon growth through actin filament polymerization and this growth is driven by axonal localization of the mRNA encoding the prenylated CDC42 isoform (Prenyl-Cdc42). Here, we show that axonal Prenyl-Cdc42 mRNA transport and translation are decreased by growth-inhibiting stimulation and increased by growth-promoting stimulation. In contrast, axonal RhoA mRNA transport and translation are increased by growth inhibition but unaffected by growth promotion. Localized increase in KHSRP in response to growth inhibitory stimulation, through elevation of intracellular Ca²⁺, promotes decay of axonal Prenyl-Cdc42 mRNA. Distinct 3'UTR motifs regulate transport and stability of axonal Prenyl-Cdc42 mRNA. KHSRP protein binds to a Prenyl-Cdc42 mRNA motif within nt 801-875 and the mRNA is remarkably increased in axons of Khsrp ^-/- mice. Selective depletion of Prenyl-Cdc42 mRNA from axons reverses the accelerated axon regeneration seen in Khsrp ^-/- mice.