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Vol. 20, Issue 4, 1167-1179, February 15, 2009

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Dorsal Root Ganglion Neurons React to Semaphorin 3A Application through a Biphasic Response that Requires Multiple Myosin II Isoforms

Jacquelyn A. Brown^*, Robert B. Wysolmerski, and Paul C. Bridgman^*

*Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110; and Department of Neurobiology and Anatomy, and the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Science Center, West Virginia University School of Medicine, Morgantown, WV 26506-9104

Submitted January 23, 2008; Revised October 31, 2008; Accepted December 11, 2008
Monitoring Editor: Paul Forscher

Growth cone responses to guidance cues provide the basis for neuronal pathfinding. Although many cues have been identified, less is known about how signals are translated into the cytoskeletal rearrangements that steer directional changes during pathfinding. Here we show that the response of dorsal root ganglion (DRG) neurons to Semaphorin 3A gradients can be divided into two steps: growth cone collapse and retraction. Collapse is inhibited by overexpression of myosin IIA or growth on high substrate-bound laminin-1. Inhibition of collapse also prevents retractions; however collapse can occur without retraction. Inhibition of myosin II activity with blebbistatin or by using neurons from myosin IIB knockouts inhibits retraction. Collapse is associated with movement of myosin IIA from the growth cone to the neurite. Myosin IIB redistributes from a broad distribution to the rear of the growth cone and neck of the connecting neurite. High substrate-bound laminin-1 prevents or reverses these changes. This suggests a model for the Sema 3A response that involves loss of growth cone myosin IIA to facilitate actin meshwork instability and collapse, followed by myosin IIB concentration at the rear of the cone and neck region where it associates with actin bundles to drive retraction.

Address correspondence to: Paul C. Bridgman (bridgmap{at}pcg.wustl.edu).

Abbreviations used: MII, myosin II; Sema 3A, Semaphorin 3A; Bleb, blebbistatin; lam-1, Laminin-1; MLC, myosin light chain; PLO, poly-L-ornithine; ROCK, Rho kinase.

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