MAR 19, 2014 12:00 PM PDT

Src Regulation of Lamellipodia, Filopodia, and Substrate-Cytoskeletal Coupling in Neuronal Growth Cones

Presented At Neuroscience
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  • Associate Professor, Department of Biological Sciences, Purdue University
      Dr. Daniel Suter studied Biology at the ETH Zurich in Switzerland, receiving an MS degree in Biological Sciences in 1988. After pursuing additional training in Biology and Chemistry Education at the ETH Zurich, he conducted graduate research on neuronal cell adhesion molecules with Prof. Peter Sonderegger in the Department of Biochemistry at the University of Zurich.  After receiving a PhD in Biochemistry in 1995, he joined the laboratory of Prof. Paul Forscher at Yale University as a Postdoctoral fellow with support from the Swiss National Science Foundation and the Roche Research Foundation. During his time at Yale University, Dr. Suter made significant contributions to the understanding of the underlying mechanisms of neuronal growth cone motility and guidance, using quantitative high-resolution live cell imaging techniques. For example, he provided the first direct experimental evidence that support the model of substrate-cytoskeletal coupling during growth cone migration.
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      <br />In 2003, he started his own lab at Purdue University as an Assistant Professor of Biological Sciences, continuing to unravel the basic mechanisms that control the directional movements of neuronal growth cones. His independent research program has focused on (1) the role of microtubules in growth cone guidance, (2) the dynamics and function of Src tyrosine kinase in growth cones, (3) the role of reactive oxygen species in controlling the neuronal cytoskeleton, and (4) the biomechanics of growth cones. Since 2009, Dr. Suter is an Associate Professor of Biological Sciences in the Department of Biological Sciences at Purdue University.
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    Axonal growth and pathfinding is fundamental to the development and regeneration of the nervous system. Src tyrosine kinase has been implicated in this process; however, the detailed molecular and cellular mechanisms involving Src regulation of neuronal growth cone motility are not fully understood. We have focused on two potential roles of Src: (1) control of coupling between cell adhesion receptors and the underlying actin cytoskeleton and (2) regulation of actin dynamics and organization in lamellipodia and filopodia. Src2 and the Src substrate and actin binding protein cortactin accumulate at adhesion sites induced by the Aplysia cell adhesion molecule apCAM. Tension application increases Src2 activation state, while Src inhibition uncouples apCAM from actin flow. Expression of constitutively active (CA) Src2 increases density and lateral movements of filopodia in Aplysia growth cones, while the expression of dominant negative (DN) Src2 or cortactin phosphorylation mutants have opposite effects, suggesting a positive role of Src2 and cortactin in filopodia formation and integration within the lamellipodial actin network. On the other hand, analysis of filopodial actin dynamics suggests only a minor role for Src2 and cortactin in regulating actin assembly during filopodial extension. CA Src2- and cortactin-expressing growth cones have wider lamellipodia and spend more time in leading edge protrusion compared with control growth cones, suggesting that Src2 activity enhances actin assembly in growth cone lamellipodia. In summary, our results indicate that Src2/cortactin regulate lamellipodia protrusion and filopodia formation in neuronal growth cones as well as force transduction at apCAM adhesion sites.

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