Short-hairpin RNA against PTEN enhances intrinsic growth of adult corticospinal tract axons after spinal cord injury

Program#/Poster#: 252.12/M11
Location: Hall F-J Neuroscience 2012, SfN’s 42nd annual meeting, is scheduled for Oct. 13 -17 in New Orleans at the Ernest N. Morial Convention Center.
Presentation time: Sunday, Oct 14, 2012, 4:00 PM – 5:00 PM
Authors: *K. A. ZUKOR, S. BELIN, L. YANG, C. WANG, H. NAWABI, Z. HE;
Children’s Hosp. Boston, Boston, MA
Abstract: Deletion of the Phosphatase and tensin homolog (PTEN) gene in corticospinal tract (CST) neurons via Cre-mediated recombination dramatically enhances their intrinsic regenerative ability and enables many of them to regrow axons through and beyond a spinal cord injury (Nat Neurosci, 2010, 13: 1075). This strategy requires the recipient to have a targeted mutation that inserts loxP sites around the PTEN gene. To broaden the versatility of this treatment, we tested whether RNA interference could be used to silence PTEN rather than gene deletion. We generated an adeno-associated virus that expresses a short-hairpin RNA sequence that has been previously shown to effectively knock-down PTEN protein expression in mice (AAV-shPTEN, J Neurosci, 2011, 31:4345). We injected this virus into the motor cortex of wild type mice, analyzed axon regeneration after a full crush spinal cord injury and compared results to those obtained from PTEN floxed/floxed mice injected with a virus expressing Cre (positive control) and appropriate negative controls. Whereas few to no axons were seen beyond the lesion in negative control mice, robust regeneration was seen in many of the animals injected with the AAV-shPTEN virus. Amounts were similar to the amounts seen in positive control mice. These results suggest that PTEN can be effectively silenced post-transcriptionally in CST neurons to enhance intrinsic axon growth after spinal cord injury and thus, open the door for testing this strategy in mammals in which targeted mutagenesis is not possible or practical, including humans. This tool will also give us more flexibility in testing combinations of therapies aimed at boosting intrinsic growth as well as altering the lesion environment.

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