Klf2-Vav1-Rac1 axis promotes axon regeneration after peripheral nerve injury

Increasing the intrinsic regeneration potential of neurons is the key to promote axon regeneration and repair of nerve injury. Therefore, identifying the molecular switches that respond to nerve injury may play critical role in improving intrinsic regeneration ability. The mechanisms by which injury unlocks the intrinsic axonal growth competence of mature neurons are not well understood. The present study identified the key regulatory genes after sciatic nerve crush injury by RNA sequencing (RNA-Seq) and found that the hub gene Vav1 was highly expressed at both early response and regenerative stages of sciatic nerve injury. Furthermore, Vav1 was required for axon regeneration of dorsal root ganglia (DRG) neurons and functional recovery. Krüppel-like factor 2 (Klf2) was induced by retrograde Ca2+ signaling from injured axons and could directly promote Vav1 transcription in adult DRG neurons. The increased Vav1 then promoted axon regeneration by activating Rac1 GTPase independent of its tyrosine phosphorylation. Collectively, these findings break through previous limited cognition of Vav1, and first reveal a crucial role of Vav1 as a molecular switch in response to axonal injury for promoting axon regeneration, which might further serve as a novel molecular therapeutic target for clinical nerve injury repair. •Hub gene Vav1 is elevated in DRG neurons after peripheral nerve injury•Vav1 is required for axon regeneration and functional recovery of DRG neurons•Transcription factor Klf2 regulates Vav1 during injury response•Vav1 promotes axon regeneration by activating Rac1 GTPase