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The Journal of Neuroscience, May 24, 2006, 26(21):5727-5732; doi:10.1523/JNEUROSCI.5229-05.2006

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Brief Communications
Functional and Selective RNA Interference in Developing Axons and Growth Cones

Ulrich Hengst, Llewellyn J. Cox, Evan Z. Macosko, and Samie R. Jaffrey

Department of Pharmacology, Weill Medical College, Cornell University, New York, New York 10021

Correspondence should be addressed to Samie R. Jaffrey at the above address. Email: srj2003{at}med.cornell.edu

Developing axons and growth cones contain "local" mRNAs that are translated in response to various extracellular signaling molecules and have roles in several processes during axonal development, including axonal pathfinding, orientation of axons in chemotactic gradients, and in the regulation of neurotransmitter release. The molecular mechanisms that regulate mRNA translation within axons and growth cones are unknown. Here we show that proteins involved in RNA interference (RNAi), including argonaute-3 and argonaute-4, Dicer, and the fragile X mental retardation protein, are found in developing axons and growth cones. These proteins assemble into functional RNA-induced silencing complexes as transfection of small interfering RNAs selectively into distal axons results in distal axon-specific mRNA knock-down, without reducing transcript levels in proximal axons or associated diffusion of small interfering RNA into proximal axons or cell bodies. RhoA mRNA is localized to axons and growth cones, and intra-axonal translation of RhoA is required for growth cone collapse elicited by Semaphorin 3A (Sema3A), an axonal guidance cue. Selective knock-down of axonal RhoA mRNA abolishes Sema3A-dependent growth cone collapse. Our results demonstrate functional and potent RNAi in axons and identify an approach to spatially regulate mRNA transcripts at a subcellular level in neurons.

Key words: RhoA; RNA interference; small interfering RNA; Dicer; Fragile X mental retardation protein; axons; growth cones

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Received Dec. 7, 2005; revised March 30, 2006; accepted April 19, 2006.

Correspondence should be addressed to Samie R. Jaffrey at the above address. Email: srj2003{at}med.cornell.edu

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