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 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.
Authors
- Courtney N. Buchanan (ORCID: https://orcid.org/0000-0003-4197-1244)
- Elizabeth Thames (ORCID: https://orcid.org/0000-0003-0120-7241)
- Nora I. Perrone‐Bizzozero (ORCID: https://orcid.org/0000-0002-7608-1332)
- Terika P. Smith (ORCID: https://orcid.org/0000-0002-1058-0753)
- Jessica Larsen (ORCID: https://orcid.org/0000-0003-2756-9523)
- Matthew D. Zdradzinski (ORCID: https://orcid.org/0000-0002-2847-2961)
- Jeffery L. Twiss (ORCID: https://orcid.org/0000-0001-7875-6682)
- Samaneh Matoo (ORCID: https://orcid.org/0000-0002-1326-5900)
- Lauren S. Vaughn (ORCID: https://orcid.org/0000-0003-2282-6738)
- Qun Lu (ORCID: https://orcid.org/0000-0003-3545-7142)
- Seung Joon Lee (ORCID: https://orcid.org/0000-0001-6690-2830)
- Kayleigh Trumbull (ORCID: https://orcid.org/0009-0002-6866-3372)
- Davis Noblitt (ORCID: https://orcid.org/0009-0000-9877-3447)
- Ashley Loomis (ORCID: https://orcid.org/0009-0007-1229-2572)
Institutions
- Biogen (United States) (US)
- University of South Carolina (US)
- University of New Mexico (US)
- NeuroDevelopment Center (US)
- Clemson University (US)
Publication Details
- Journal
- PLoS Genetics
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1371/journal.pgen.1011916
- Primary Topic
- Nerve injury and regeneration
- Type
- article
- Field-Weighted Citation Impact
- 0.00