KHSRP-mediated decay of axonally localized prenyl-Cdc42 mRNA slows nerve regeneration

TL;DR

This study shows that the protein KHSRP slows nerve regeneration by degrading a specific mRNA in axons, which could lead to new treatments for nerve injuries.

Contribution

The study identifies KHSRP as a key regulator of axonal Prenyl-Cdc42 mRNA decay, linking it to nerve regeneration speed.

Findings

KHSRP promotes decay of axonal Prenyl-Cdc42 mRNA in response to growth-inhibiting signals.

Khsrp-/- mice show accelerated nerve regeneration due to increased axonal Prenyl-Cdc42 mRNA.

Depletion of Prenyl-Cdc42 mRNA in Khsrp-/- mice slows axon regeneration.

Abstract

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 levels and the mRNA’s 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-inhibiting but unaffected by growth-promoting stimuli. Localized increase in KHSRP in response to growth inhibitory stimulation, through elevation of intracellular Ca2+, promotes decrease in axonal levels of Prenyl-Cdc42 mRNA. Distinct 3’UTR motifs regulate transport and axonal levels of 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. Depletion of the mRNA from sciatic nerve indicates that the increased axonal Prenyl-CDC42 contributes to the accelerated nerve regeneration when neuronal KHSRP is depleted.

Regrowth of the axons making up peripheral nerves after traumatic injury is possible but the regeneration is too slow to return full functionality over anything beyond a few centimeters distance in the nerve. This results in loss of sensations and movements distal to the injury and can lead to pathological pain. Better understanding of the molecular processes that modulate regrowth after injury could lead to new therapeutic strategies for accelerating nerve regeneration and have benefits for brain and spinal cord injury where regeneration of axons completely fails. CDC42 proteins are known to promote axon growth, which was recently shown to be driven by localized synthesis of the prenylated CDC42 isoform in axons. We find that growth-promoting factors stimulate translation of the axonal CDC42 mRNA while growth-inhibiting stimuli decrease translation by promoting decay of the mRNA. The RNA binding protein KHSRP targets axonal CDC42 mRNA for degradation. KHSRP is known to slow axon regeneration and mice lacking KHSRP show accelerated nerve regeneration. We find that removing CDC42 mRNA from the injured axons of KHSRP knockout mice slows their axon regeneration, indicating that KHSRP-mediated decay of axonal CDC42 mRNA slows nerve growth.

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