title: Krüppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract.
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 up-regulate 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.
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53201, USA. murray.blackmore@marquette.edu
authors.forename: Murray G
authors.initials: MG
authors.lastname: Blackmore
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wang
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Lerch
authors.forename: Dario
authors.initials: D
authors.lastname: Motti
authors.forename: Yi Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Shields
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Goldberg
authors.forename: Vance P
authors.initials: VP
authors.lastname: Lemmon
authors.forename: John L
authors.initials: JL
authors.lastname: Bixby
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D005047:Etoposide; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008163:Luminescent Measurements / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D016501:Neurites / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D011712:Pyramidal Tracts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015533:Transcriptional Activation
chemical_list: D017405:Herpes Simplex Virus Protein Vmw65; C426008:Klf7 protein, mouse; D051741:Kruppel-Like Transcription Factors; D049452:Green Fluorescent Proteins; D005047:Etoposide