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The Journal of Neuroscience, May 23, 2007, 27(21):5823-5834; doi:10.1523/JNEUROSCI.1135-07.2007

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Development/Plasticity/Repair
Cytoplasmic Dynein and LIS1 Are Required for Microtubule Advance during Growth Cone Remodeling and Fast Axonal Outgrowth

Peter W. Grabham,^1,3,4 * Garrett E. Seale,^2,4 * Malika Bennecib,^2,4 Daniel J. Goldberg,^1,4 and Richard B. Vallee^2,4

Departments of ¹Pharmacology and ²Pathology and Cell Biology, and Centers for ³Radiological Research and ⁴Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Correspondence should be addressed to Dr. Richard B. Vallee, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, Physicians and Surgeons 15-409, 630 West 168th Street, New York, NY 10032. Email: rv2025{at}columbia.edu

Recent evidence has implicated dynein and its regulatory factors dynactin and LIS1 in neuronal and non-neuronal cell migration. In the current study we sought to test whether effects on neuronal cell motility might reflect, in part, a role for these proteins in the growth cone. In chick sensory neurons subjected to acute laminin treatment dynein, dynactin, and LIS1 were mobilized strikingly and rapidly to the leading edge of the growth cone, where they were seen to be associated with microtubules converging into the laminin-induced axonal outgrowths. To interfere acutely with LIS1 and dynein function and to minimize secondary phenotypic effects, we injected antibodies to these proteins just before axon initiation. Antibody to both proteins produced an almost complete block of laminin-induced growth cone remodeling and the underlying reorganization of microtubules. Penetration of microtubules into the peripheral zone of differentiating axonal growth cones was decreased dramatically by antibody injection, as judged by live analysis of enhanced green fluorescent protein-tubulin and the microtubule tip-associated EB3 (end-binding protein 3). Dynein and LIS1 inhibition had no detectable effect on microtubule assembly but reduced the ability of microtubules to resist retrograde actin flow. In hippocampal neurons dynein, dynactin, and LIS1 were enriched in axonal growth cones at stage 3, and both growth cone organization and axon elongation were altered by LIS1 RNA interference. Together, our data indicate that dynein and LIS1 play a surprisingly prominent role in microtubule advance during growth cone remodeling associated with axonogenesis. These data may explain, in part, the role of these proteins in brain developmental disease and support an important role in diverse aspects of neuronal differentiation and nervous system development.

Key words: growth cone; dynein; LIS1; microtubule; axon; outgrowth

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Received May 8, 2006; accepted April 17, 2007.

Correspondence should be addressed to Dr. Richard B. Vallee, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, Physicians and Surgeons 15-409, 630 West 168th Street, New York, NY 10032. Email: rv2025{at}columbia.edu

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