title: Genetic Deletion of the Transcriptional Repressor NFIL3 Enhances Axon Growth In Vitro but Not Axonal Repair In Vivo.
abstract: Axonal regeneration after injury requires the coordinated expression of genes in injured neurons. We previously showed that either reducing expression or blocking function of the transcriptional repressor NFIL3 activates transcription of regeneration-associated genes Arg1 and Gap43 and strongly promotes axon outgrowth in vitro. Here we tested whether genetic deletion or dominant-negative inhibition of NFIL3 could promote axon regeneration and functional recovery after peripheral nerve lesion in vivo. Contrary to our expectations, we observed no changes in the expression of regeneration-associated genes and a significant delay in functional recovery following genetic deletion of Nfil3. When NFIL3 function was inhibited specifically in dorsal root ganglia prior to sciatic nerve injury, we observed a decrease in regenerative axon growth into the distal nerve segment rather than an increase. Finally, we show that deletion of Nfil3 changes sciatic nerve lesion-induced expression in dorsal root ganglia of genes that are not typically involved in regeneration, including several olfactory receptors and developmental transcription factors. Together our findings show that removal of NFIL3 in vivo does not recapitulate the regeneration-promoting effects that were previously observed in vitro, indicating that in vivo transcriptional control of regeneration is probably more complex and more robust against perturbation than in vitro data may suggest.
authors.affiliation: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: Loek R
authors.initials: LR
authors.lastname: van der Kallen
authors.affiliation: Department of Neuroregeneration, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: Eggers
authors.affiliation: Department of Neuroregeneration, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
authors.forename: Erich M
authors.initials: EM
authors.lastname: Ehlert
authors.affiliation: Department of Neuroregeneration, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Verhaagen
authors.affiliation: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: van Kesteren
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D063990:Gene Ontology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009409:Nerve Crush; D009416:Nerve Regeneration; D009474:Neurons / Q000378:metabolism; D017208:Rats, Wistar; D020127:Recovery of Function; D012097:Repressor Proteins / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries / Q000473:pathology / Q000503:physiopathology
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C558007:NFIL3 protein, rat; C497441:Nfil3 protein, mouse; D012097:Repressor Proteins