Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons.
Rho-GTPase has been implicated in axon outgrowth. However, not all of the critical steps controlled by Rho have been well characterized. Using cultured cerebellar granule neurons, we show here that stromal cell-derived factor (SDF)-1alpha, a neural chemokine, is a physiological ligand that can turn on two distinct Rho-dependent pathways with opposite consequences. A low concentration of the ligand stimulated a Rho-dependent pathway that mediated facilitation of axon elongation. In contrast, Rho/ROCK activation achieved by a higher concentration of SDF-1alpha caused repression of axon formation and induced no more increase in axon length. However, even at this higher concentration a Rho-dependent axon elongating activity could be recovered upon removal of ROCK activity using Y-27632. SDF-1alpha-induced axon elongating activity under ROCK inhibition was replicated by the dominant-active form of the mammalian homologue of the Drosophila gene Diaphanous (mDia)1 and counteracted by its dominant-negative form. Furthermore, RNAi knockdown of mDia1 abolished SDF-1alpha-induced axon elongation. Together, our results support a critical role for an SDF-1alpha/Rho/mDia1 pathway in mediating axon elongation.
Arakawa
Yoshiki
Y
Dept. of Pharmacology, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8315, Japan.
Bito
Haruhiko
H
Furuyashiki
Tomoyuki
T
Tsuji
Takahiro
T
Takemoto-Kimura
Sayaka
S
Kimura
Kazuhiro
K
Nozaki
Kazuhiko
K
Hashimoto
Nobuo
N
Narumiya
Shuh
S
D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000080865:Formins; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D054460:rho-Associated Kinases
D000199:Actins; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C491464:Diap1 protein, mouse; D004791:Enzyme Inhibitors; D000080865:Formins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins