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Published on: May 5, 2018
KHSRP-mediated decay of axonally localized prenyl-Cdc42 mRNA slows nerve regeneration
Matthew D Zdradzinski1, Lauren S Vaughn1, Samaneh Matoo1
1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, United States of America.
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.
Insights
Growth inhibition reduces axonal Prenyl-Cdc42 mRNA, while KHSRP protein binding decreases its levels. Depleting KHSRP accelerates nerve regeneration by increasing axonal Prenyl-CDC42.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Axon growth is regulated by the small GTPase CDC42, involving actin polymerization.
- Axonal localization and translation of Prenyl-Cdc42 mRNA drive axon growth.
- RhoA signaling also plays a role in axonal responses to growth stimuli.
Purpose of the Study:
- To investigate the regulation of axonal Prenyl-Cdc42 mRNA levels and translation.
- To determine the role of KHSRP in controlling axonal Prenyl-Cdc42 mRNA.
- To elucidate the mechanisms underlying nerve regeneration influenced by KHSRP and Prenyl-CDC42.
Main Methods:
- Quantitative analysis of axonal mRNA levels under different stimulation conditions.
- Investigation of mRNA transport and translation regulation.
- KHSRP protein binding assays and analysis of Khsrp-/- mouse models.
- Sciatic nerve regeneration studies.
Main Results:
- Axonal Prenyl-Cdc42 mRNA levels and translation decrease with growth-inhibiting stimuli and increase with growth-promoting stimuli.
- Axonal RhoA mRNA transport and translation increase with growth inhibition.
- KHSRP, upregulated by calcium signaling, binds Prenyl-Cdc42 mRNA, reducing its axonal levels.
- Khsrp-/- mice exhibit increased axonal Prenyl-Cdc42 mRNA, leading to accelerated nerve regeneration.
Conclusions:
- Axonal Prenyl-Cdc42 mRNA levels are dynamically regulated by neuronal stimulation and KHSRP.
- KHSRP acts as a negative regulator of axonal Prenyl-Cdc42 mRNA levels.
- KHSRP depletion promotes nerve regeneration by increasing axonal Prenyl-CDC42, highlighting its therapeutic potential.
