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Axonal/Dendritic Growth and Circuit Formation

開催日 2014/9/13
時間 14:00 - 15:00
会場 Poster / Exhibition(Event Hall B)

Dock6 regulates switching from axon extension to branching

  • P3-062
  • 宮本 幸 / Yuki Miyamoto:1 鳥居 知宏 / Tomohiro Torii:1 田上 昭人 / Akito Tanoue:1 山内 淳司 / Junji Yamauchi:1,2 
  • 1:国立成育医療センター研究所 / Mol. Pharm. Group, Dept. of Pharmacology, Natl. Res. Inst. Child Health Dev. 2:東京医科歯科大・医歯学総合研究科 / Grad. School of Medical and Dental Sci., Tokyo Medical and Dental Univ. 

The navigation of peripheral nervous system (PNS) neuronal axons involves active axon elongation, and in turn branching, which occurs when axons arrive at their target fields. The process requires continuous morphological changes, yet its underlying molecular mechanisms still remain to be understood. Rho GTPases are one class of signaling molecules that control such changes. Yet there remain missing links in the pathway coupling extracellular signals to Rho GTPases. We previously characterized Dock6 as an atypical Dock180-related guanine-nucleotide exchange factor for Rac and Cdc42. Here, we demonstrate that, in dorsal root ganglion (DRG) neurons, axon extension and branching are regulated by phosphorylation and dephosphorylation of the single serine residue of Dock6. We found that, during initial axon outgrowth, Dock6 forms a complex with PP2A, which inhibits the phosphorylation of Dock6 by Akt, allowing axons to extend. As axons grow, Akt abundance is increased, and Akt binds to Dock6 instead of PP2A and phosphorylates Dock6 at Ser1194, thereby decreasing the GEF activity of Dock6 and inhibiting axon growth. Rescue experiments indicated that the phosphorylation status of Dock6 switched DRG neurons from axon extension to branching. Additionally, Dock6 shRNA transgenic (TG) mice exhibited a phenotype characterized by shortened peripheral neuronal fibers, which extend from the ganglia to the ventral roots, compared with control nontransgenic littermates. Also, we observed delayed extension of neuronal fibers in Dock6 shRNA TG mice after sciatic nerve injury, suggesting the involvement of Dock6 both in normal development and after injury. Thus, regulation of the phosphorylation status of Dock6 by Akt and PP2A determines whether it promotes axon extension or branching, and proper timing of targeting this pathway is essential for nerve regeneration after injury.

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