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KHSRP-mediated Decay of Axonally Localized Prenyl-Cdc42 mRNA Slows Nerve Regeneration
M D Zdradzinski1, Lauren S Vaughn1, Samaneh Matoo1
1Department of Biological Sciences, University of South Carolina, Columbia, SC 20208 USA.
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 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.
Insights
Axon growth is regulated by the transport and translation of Prenyl-Cdc42 mRNA, influenced by growth signals. KHSRP protein promotes Prenyl-Cdc42 mRNA decay, impacting axon regeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- The small GTPase CDC42 is crucial for axon growth, mediated by actin polymerization.
- Axon growth is dependent on the localized transport and translation of specific mRNAs, such as Prenyl-Cdc42 mRNA.
Purpose of the Study:
- To investigate the regulation of axonal Prenyl-Cdc42 mRNA transport and translation in response to growth-modulating stimuli.
- To identify the mechanisms controlling Prenyl-Cdc42 mRNA stability and transport in axons.
- To elucidate the role of KHSRP in regulating Prenyl-Cdc42 mRNA and its impact on axon regeneration.
Main Methods:
- Analysis of axonal mRNA transport and translation under varying growth conditions.
- Investigation of the role of KHSRP in mRNA decay and binding.
- Utilizing Khsrp knockout mouse models to assess axon regeneration.
Main Results:
- Axonal Prenyl-Cdc42 mRNA transport and translation are modulated by growth-promoting and inhibiting stimuli.
- Growth inhibition, via increased intracellular Ca2+ and KHSRP, leads to Prenyl-Cdc42 mRNA decay.
- KHSRP binds to a specific motif in Prenyl-Cdc42 mRNA, and its absence results in increased axonal mRNA and enhanced regeneration.
Conclusions:
- Axonal mRNA dynamics, specifically for Prenyl-Cdc42, are key regulators of axon growth and regeneration.
- KHSRP acts as a negative regulator of Prenyl-Cdc42 mRNA, influencing axon regeneration.
- Targeting KHSRP or Prenyl-Cdc42 mRNA could be a therapeutic strategy for enhancing axon repair.
