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J. Biol. Chem., Vol. 282, Issue 22, 16423-16433, June 1, 2007

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Neogenin-RGMa Signaling at the Growth Cone Is Bone Morphogenetic Protein-independent and Involves RhoA, ROCK, and PKC^*

Sabine Conrad, Harald Genth, Fred Hofmann, Ingo Just, and Thomas Skutella^¶1

From the ^¶Centre for Regenerative Medicine and Biology, 72074 Tübingen, the Institute of Anatomy, Department of Experimental Embryology, Section of Tissue Engineering, 72074 Tübingen, and the Institute of Toxicology, Hannover Medical School, 30625 Hannover, Germany

The repulsive guidance molecule RGMa has been shown to induce outgrowth inhibition of neurites by interacting with the transmembrane receptor neogenin. Here we show that RGMa-induced growth cone collapse is mediated by activation of the small GTPase RhoA, its downstream effector Rho kinase and PKC. In contrast to DRG cultures from neogenin^-/- mice, in which no RGMa-mediated growth cone collapse and activation of RhoA occurred, treatment of wild type DRG neurites with soluble RGMa led to a marked activation of RhoA within 3 min followed by collapse, but left Rac1 and Cdc42 unaffected. Furthermore, preincubation of DRG axons with the bone morphogenetic protein (BMP) antagonist noggin had no effect on RGMa-mediated growth cone collapse, implying that the role of RGM in axonal guidance is neogenin- and not BMP receptor-dependent. Pretreatment with 1) C3-transferase, a specific inhibitor of the Rho GTPase; 2) Y-27632, a specific inhibitor of Rho kinase; and 3) Gö6976, the general PKC inhibitor, strongly inhibited the collapse rate of PC12 neurites. Growth cone collapse induced by RGMa was abolished by the expression of dominant negative RhoA, but not by dominant negative Rac1. In contrast to RGMa, netrin-1 induced no growth cone retraction but instead reduced RGMa-mediated growth cone collapse. These results suggest that activation of RhoA, Rho kinase, and PKC are physiologically relevant and important elements of the RGMa-mediated neogenin signal transduction pathway involved in axonal guidance.

Received for publication, November 12, 2006 , and in revised form, March 23, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and movies 1 and 2.

¹ To whom correspondence should be addressed: Centre for Regenerative Medicine and Biology, Dept. of Experimental Embryology, Section for Tissue Engineering, Österbergstr. 3, 72074 Tübingen, Germany. Tel.: 07071-29-72186; Fax: 07071-29-5124; E-mail: Thomas.Skutella{at}uni-tuebingen.de.

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