期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 19, 页码 7517-7522出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1120684109
关键词
gene therapy; spinal cord injury; adeno associated virus; laser capture microdissection
资金
- James and Esther King Biomedical Research Program [JEK09KW-05]
- Craig H. Neilsen Foundation
- US Army [W81XWH-05-1-0061]
- National Institutes of Health [HD057521, NS059866, NEI EY020913, P30-EY014801]
- American Health Assistance Foundation
- Research to Prevent Blindness
- Buoniconti Fund
- Walter G. Ross Distinguished Chairs in Developmental Neuroscience
- Ophthalmic Research
Axon regeneration in the central nervous system normally fails, in part because of a developmental decline in the intrinsic ability of CNS projection neurons to extend axons. Members of the KLF family of transcription factors regulate regenerative potential in developing CNS neurons. Expression of one family member, KLF7, is down-regulated developmentally, and overexpression of KLF7 in cortical neurons in vitro promotes axonal growth. To circumvent difficulties in achieving high neuronal expression of exogenous KLF7, we created a chimera with the VP16 transactivation domain, which displayed enhanced neuronal expression compared with the native protein while maintaining transcriptional activation and growth promotion in vitro. Overexpression of VP16-KLF7 overcame the developmental loss of regenerative ability in cortical slice cultures. Adult corticospinal tract (CST) neurons failed to upregulate KLF7 in response to axon injury, and overexpression of VP16-KLF7 in vivo promoted both sprouting and regenerative axon growth in the CST of adult mice. These findings identify a unique means of promoting CST axon regeneration in vivo by reengineering a developmentally down-regulated, growth-promoting transcription factor.
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