Krüppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract

Murray G. Blackmore, Zimei Wang, Jessica K. Lerch, Dario Motti, Yi Ping Zhang, Christopher B. Shields, Jae Lee, Jeffrey L. Goldberg, Vance Lemmon, John Bixby

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)7517-7522
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number19
DOIs
StatePublished - May 8 2012

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Keywords

  • Adeno associated virus
  • Gene therapy
  • Laser capture microdissection
  • Spinal cord injury

ASJC Scopus subject areas

  • General

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