βPix Guanine Nucleotide Exchange Factor Regulates Regeneration of Injured Peripheral Axons

초록

Axon regeneration is essential for successful recovery after peripheral nerve injury. Although growth cone reformation and axonal extension are crucial steps in axonal regeneration, the regulatory mechanisms underlying these dynamic processes are poorly understood. Here, we identify beta Pix (Arhgef7), the guanine nucleotide exchange factor for Rac1 GTPase, as a regulator of axonal regeneration. After sciatic nerve injury in mice, the expression levels of beta Pix increase significantly in nerve segments containing regenerating axons. In regrowing axons, beta Pix is localized in the peripheral domain of the growth cone. Using beta Pix neuronal isoform knockout (NIKO) mice in which the neuronal isoforms of beta Pix are specifically removed, we demonstrate that beta Pix promotes neurite outgrowth in cultured dorsal root ganglion neurons and in vivo axon regeneration after sciatic nerve crush injury. Activation of cJun and STAT3 in the cell bodies is not affected in beta Pix NIKO mice, supporting the local action of beta Pix in regenerating axons. Finally, inhibiting Src, a kinase previously identified as an activator of the beta Pix neuronal isoform, causes axon outgrowth defects in vitro, like those found in the beta Pix NIKO neurons. Altogether, these data indicate that beta Pix plays an important role in axonal regrowth during peripheral nerve regeneration.

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