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Correspondence to: James R. Bamburg, Dept. of Biochemistry and Molecular Biology, Colorado State University, 1870 Campus Delivery, Fort Collins, CO 80523-1870. E-mail: jbamburg@lamar.colostate.edu
SINCE THE DISCOVERY of the neuron as the cellular component of the nervous system more than 100 years ago, scientists have attempted to unlock the mysteries of how the nervous system develops its myriad of synaptic connections. Santiago Ramón y Cajal was the first to identify many of the complex types of neurons that exist in the central and peripheral nervous systems (
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Structure and Organization of the Growth Cone |
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The growth cone has two major domains characterized by the cytoskeletal components found mainly therein. The peripheral domain (Fig 1a1c, Fig p) is rich in actin filaments, which are organized into different types of structures. The filaments in parallel bundles are called ribs, if they do not protrude from the body of the growth cone, or filopodia, if they extend into finger-like projections. In between these rib structures at the membrane are often found a meshwork of filaments in regions that are extending forward. These membrane expansions are called lamellipodia, if they are closely associated with the substratum, or membrane ruffles, if they appear on the apical surface of the growth cone. Ruffles are usually formed from lamellipodia that fail to adhere to the substratum and collapse back into the growth cone. A veil is a region of expanding membrane between two filopodia. Veils can adhere to the substratum to generate a lamellipodium, or they can lift back and generate a ruffle. Actin within the p domain is undergoing dynamic assembly that lead to membrane protrusion. Recruitment and activation of myosin lead to contraction and the retrograde flow of actin back towards the central (c) domain (
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The central domain (Fig 1a1c) is rich in microtubules and membranous organelles. Microtubules are oriented with their plus ends towards or within the p domain (
Microtubules extending into this p domain appear to be important for neurite pathfinding (
The formation of focal adhesions is coupled with the actin assembly-based protrusion of membrane at the leading edge of growth cones (
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Mechanisms of Regulating Growth Cone Guidance |
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The mechanisms by which extracellular guidance cues regulate growth cone turning and pathfinding have not been completely elucidated for any single guidance molecule, although significant progress in this area has been made during the past few years. The pioneering studies of Alan Hall and co-workers, using fibroblasts as a model system, demonstrated that Rho family GTPases are master regulators of actin organization (
Recent studies also suggest that local translation of mRNA in axons and dendrites can also play a key role in regulating growth cone navigation. In response to repulsive guidance cues, local protein synthesis appears to be needed to bring about the morphological changes in growth cone structure in response to sema 3A or netrin-1 (
The known molecular mechanisms involved in growth cone motility and neurite extension provide several possible modes for regulation of growth cone navigation. Extracellular guidance cues could be presented in patterns whereby only a single response (attraction or repulsion) of the growth cone is elicited. In regions where mixed cues are present, growth cones must integrate these signals into a single growth response. Such integration could occur at several levels, including the following: (a) localization, activity, or expression of guidance cue receptors; (b) signal transduction from the receptor to the Rho family GTPases; (c) regulation of the kinases and phosphatases downstream of the GTPases; (d) regulation of proteins that control cytoskeletal dynamics; (e) regulation of vesicle formation and delivery; (f) targeting specific mRNAs to growth cones; (g) regulation of growth cone adhesion; and (h) activation and recruitment of the contractile motors. There is some compelling evidence that involves each of these steps.
The papers that follow are review articles based on a symposium at the Sixth Joint Meeting of The Japan Society of Histochemistry and Cytochemistry and The Histochemical Society held in Seattle, Washington in July, 2002. These reviews focus on some of the areas described above. They start with a focus inside the growth cone looking at the molecules and pathways regulating the actin cytoskeleton, the role of myosin II isoforms in growth cone activity, and the role of SNARE proteins in neuronal outgrowth. They then address how neurotrophic factors and repulsive cues signal growth cones and conclude with a look at how an extracellular gradient of repulsive cues affects growth cone behavior.
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Footnotes |
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1 Presented as part of the Cytoskeletal Dynamics and Path Finding of Neuronal Growth Cones Symposium, 6th Joint Meeting of the Japan Society of Histochemistry and Cytochemistry and the Histochemical Society, University of Washington, Seattle, WA, July 1821, 2002.
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Acknowledgments |
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Supported by the Alzheimer's Association (grant IIRG-01-2730) and the National Institutes of Health (grants GM35126 and NS40371).
I thank Barbara Bernstein, O'Neil Wiggan, and Patrick Sarmiere for valuable discussions and comments on this article.
Received for publication September 19, 2002; accepted October 25, 2002.
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