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Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons.

Arakawa Y, Bito H, Furuyashiki T, Tsuji T, Takemoto-Kimura S, Kimura K, Nozaki K, Hashimoto N, Narumiya S - J. Cell Biol. (2003)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Pharmacology, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8315, Japan.

ABSTRACT
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.

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Proposed model for the role of mDia in SDF-1α– dependent axon outgrowth in cultured cerebellar granule neurons. Usually Rho and Rac antagonistically controls axon outgrowth. During the very early stages in the primary culture, ROCK action predominates to favor suppression of precocious outgrowth of axons from the cerebellar granule cells. However, as these neurons express a high amount of mDia1 gradual decline in ROCK activity facilitates expression of Rho-dependent mDia1 activity and a subsequent recruitment of a signaling complex, which in concert with the Rac-dependent signaling cascade may help the transition from inhibition to stimulation of axon outgrowth and elongation. Thus, the SDF-1α/Rho/mDia1 pathway may play a critical role in defining and modulating the balance between the Rho- and Rac-based signaling pathways during axon outgrowth.
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fig10: Proposed model for the role of mDia in SDF-1α– dependent axon outgrowth in cultured cerebellar granule neurons. Usually Rho and Rac antagonistically controls axon outgrowth. During the very early stages in the primary culture, ROCK action predominates to favor suppression of precocious outgrowth of axons from the cerebellar granule cells. However, as these neurons express a high amount of mDia1 gradual decline in ROCK activity facilitates expression of Rho-dependent mDia1 activity and a subsequent recruitment of a signaling complex, which in concert with the Rac-dependent signaling cascade may help the transition from inhibition to stimulation of axon outgrowth and elongation. Thus, the SDF-1α/Rho/mDia1 pathway may play a critical role in defining and modulating the balance between the Rho- and Rac-based signaling pathways during axon outgrowth.

Mentions: Together, our data establish a critical role for the Rho/mDia1 pathway in mediating axon elongation in SDF-1α–stimulated cerebellar granule neurons, presumably in concert with Rac activity (Fig. 10) .


Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons.

Arakawa Y, Bito H, Furuyashiki T, Tsuji T, Takemoto-Kimura S, Kimura K, Nozaki K, Hashimoto N, Narumiya S - J. Cell Biol. (2003)

Proposed model for the role of mDia in SDF-1α– dependent axon outgrowth in cultured cerebellar granule neurons. Usually Rho and Rac antagonistically controls axon outgrowth. During the very early stages in the primary culture, ROCK action predominates to favor suppression of precocious outgrowth of axons from the cerebellar granule cells. However, as these neurons express a high amount of mDia1 gradual decline in ROCK activity facilitates expression of Rho-dependent mDia1 activity and a subsequent recruitment of a signaling complex, which in concert with the Rac-dependent signaling cascade may help the transition from inhibition to stimulation of axon outgrowth and elongation. Thus, the SDF-1α/Rho/mDia1 pathway may play a critical role in defining and modulating the balance between the Rho- and Rac-based signaling pathways during axon outgrowth.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172896&req=5

fig10: Proposed model for the role of mDia in SDF-1α– dependent axon outgrowth in cultured cerebellar granule neurons. Usually Rho and Rac antagonistically controls axon outgrowth. During the very early stages in the primary culture, ROCK action predominates to favor suppression of precocious outgrowth of axons from the cerebellar granule cells. However, as these neurons express a high amount of mDia1 gradual decline in ROCK activity facilitates expression of Rho-dependent mDia1 activity and a subsequent recruitment of a signaling complex, which in concert with the Rac-dependent signaling cascade may help the transition from inhibition to stimulation of axon outgrowth and elongation. Thus, the SDF-1α/Rho/mDia1 pathway may play a critical role in defining and modulating the balance between the Rho- and Rac-based signaling pathways during axon outgrowth.
Mentions: Together, our data establish a critical role for the Rho/mDia1 pathway in mediating axon elongation in SDF-1α–stimulated cerebellar granule neurons, presumably in concert with Rac activity (Fig. 10) .

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Pharmacology, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8315, Japan.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus