Rab11 and Its Effector Rab Coupling Protein Contribute to the Trafficking of beta 1 Integrins during Axon Growth in Adult Dorsal Root Ganglion Neurons and PC12 Cells

Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 09/2010; 30(35):11654-69. DOI: 10.1523/JNEUROSCI.2425-10.2010
Source: PubMed

ABSTRACT Integrins play an important part in axon growth, but integrin traffic in neurons is poorly understood. Expression of the tenascin-C-binding integrin alpha9 promotes axon regeneration. We have therefore studied the mechanism by which alpha9 integrin and its partner beta1 are trafficked along axons and at the growth cone using adult DRG neurons and PC12 cells. We have focused on the small GTPase Rab11 and its effector Rab coupling protein (RCP), as they are involved in the long-range trafficking of beta1 integrins in other cells. Rab11 colocalizes with alpha9 and other alpha integrins and with beta1 integrin in growth cones and axons, and immunopurified Rab11 vesicles contain alpha9 and beta1. Endocytosed beta1 integrins traffic via Rab11. However, Rab11 vesicles in axons are generally static, and alpha9 integrins undergo bouts of movement during which they leave the Rab11 compartment. In growth cones, alpha9 and beta1 overlap with RCP, particularly at the growth cone periphery. We show that beta1 integrin trafficking during neurite outgrowth involves Rab11 and RCP, and that manipulation of these molecules alters surface integrin levels and axon growth, and can be used to enhance alpha9 integrin-dependent neurite outgrowth. Our data suggest that manipulation of trafficking via Rab11 and RCP could be a useful strategy for promoting integrin-dependent axonal regeneration.

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Available from: Richard Eva, Jul 30, 2015
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    • "Additionally, Rab11 over-expression increases neurite elongation in NGF-treated PC12 cells and dorsal root ganglia, whereas Rab11 knockdown decreases neurite length and reduces the levels of a9 and b1 integrins in the growth cone (Eva et al. 2010). Together, these experiments suggest that active Rab11 promotes neurite elongation. "
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    • "Interestingly, the STOML3- containing vesicles do not form part of the signaling endosome pool, as they are Rab5-negative but Rab11-positive. Rab11-positive vesicles have been characterized as composing a slowly recycling endocytic compartment, and may be transported predominantly anterogradely in sensory neurons (Asca~ no et al., 2009; Eva et al., 2010). Indeed, gain or loss of function Rab11 mutants radically change vesicle behavior, but these compartments still contain STOML3 (Lapatsina et al., 2012). "
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    • "Besides CNTNAP2, we also validated ITGA9 as a direct target gene. ITGA9 has been shown to be involved in axon regeneration [34]. Exploration of STOX1A as an upstream regulator of the ITGA9 gene could possibly reveal a function for STOX1A in axon regeneration. "
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