Selective axonal translation of prenylated Cdc42 mRNA isoform supports axon growth.

The small Rho-family GTPase Cdc42 has long been known to have a role in cell motility and axon growth. The eukaryotic CDC42 gene is alternatively spliced to generate mRNAs with two different 3'UTRs that encode proteins with distinct C-termini. The C-termini of these Cdc42 proteins include CAAX and CCAX motifs for post-translational prenylation and palmitoylation, respectively. Palmitoyl-Cdc42 protein was previously shown to contribute to dendrite maturation, while the prenyl-Cdc42 protein contributes to axon specification and its mRNA was detected in neurites. Here, we show that the mRNA encoding prenyl-Cdc42 isoform preferentially localizes into PNS axons and this localization selectively increases in vivo during PNS axon regeneration. Functional studies indicate that prenyl-Cdc42 increases axon length and this requires axonal targeting of the mRNA and an intact C-terminal CaaX motif that can drive prenylation of the encoded protein. In contrast, the palmitoyl-Cdc42 has no effect on axon growth but it selectively increased dendrite length. Together, these data show that alternative splicing of the CDC42 gene product generates an axon growth promoting locally synthesized prenyl-Cdc42 protein.