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p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation

Nature Cell Biology volume 3, pages 361–367 (2001)Cite this article

Abstract

The Src tyrosine kinases have been implicated in several aspects of neural development and nervous system function; however, their relevant substrates in brain and their mechanism of action in neurons remain to be established clearly. Here we identify the potent Rho regulatory protein, p190 RhoGAP (GTPase-activating protein), as the principal Src substrate detected in the developing and mature nervous system. We also find that mice lacking functional p190 RhoGAP exhibit defects in axon guidance and fasciculation. p190 RhoGAP is co-enriched with F-actin in the distal tips of axons, and overexpressing p190 RhoGAP in neuroblastoma cells promotes extensive neurite outgrowth, indicating that p190 RhoGAP may be an important regulator of Rho-mediated actin reorganization in neuronal growth cones. p190 RhoGAP transduces signals downstream of cell-surface adhesion molecules, and we find that p190-RhoGAP-mediated neurite outgrowth is promoted by the extracellular matrix protein laminin. Together with the fact that mice lacking neural adhesion molecules or Src kinases also exhibit defects in axon outgrowth, guidance and fasciculation, our results suggest that p190 RhoGAP mediates a Src-dependent adhesion signal for neuritogenesis to the actin cytoskeleton through the Rho GTPase.

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Figure 1: Tyrosine phosphorylation of p190 RhoGAP in the nervous system.
Figure 2: Axon guidance defects in p190 RhoGAP mutant mice.
Figure 3: Development of the cerebral cortex in p190 RhoGAP mutant mice.
Figure 4: Aberrant axonal fasciculation in p190 RhoGAP mutant mice.
Figure 5: Induction of neuritogenesis in Neuro-2A cells by overexpression of p190 RhoGAP.
Figure 6: Promotion of integrin-mediated neuritogenesis by overexpression of p190 RhoGAP.

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Acknowledgements

We are grateful to V. Lemmon for the L1 antibody; K. Kosik for the MAP2 antibody; M. Lu and K. Kosik for assistance with video microscopy; M. Tessier-Lavigne for assistance with staining of spinal cord sections; E. Calautti for providing brains from src and fyn mutant mice; C. Hu for technical assistance; and members of the laboratory for helpful discussions. This work is supported by the NIH and American Cancer Society awards to J.S.

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  1. Madeleine R. Brouns and Stephen F. Matheson: These two authors contributed equally to this work

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  1. MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, 02129, Massachusetts, USA

    Madeleine R. Brouns, Stephen F. Matheson & Jeffrey Settleman

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Correspondence to Jeffrey Settleman.

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Brouns, M., Matheson, S. & Settleman, J. p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation. Nat Cell Biol 3, 361–367 (2001). https://doi.org/10.1038/35070042

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