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1. Genetic Deletion of the Transcriptional Repressor NFIL3 Enhances Axon Growth In Vitro but Not Axonal Repair In Vivo.

Author

Loek R van der Kallen, Ruben Eggers, Erich M Ehlert, Joost Verhaagen, August B Smit, and Ronald E van Kesteren

Subjects
Medicine, Science
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.

Published
2015
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2. Genome-wide gene expression and promotor binding analysis identifies NFIL3 as a repressor of C/EBP target genes in neuronal outgrowth

Author

M. J. M. Sassen, August B. Smit, Jochem Cornelis, Harold D. MacGillavry, Ronald E. van Kesteren, Joost Verhaagen, Loek R. van der Kallen, Netherlands Institute for Neuroscience (NIN), Molecular and Cellular Neurobiology, AIMMS, and Neuroscience Campus Amsterdam - Neurodegeneration

Subjects
Transcription, Genetic, Amino Acid Motifs, Molecular Sequence Data, Gene Expression, Repressor, CREB, Mice, Cellular and Molecular Neuroscience, Cell Line, Tumor, Ganglia, Spinal, Enhancer binding, Gene expression, Animals, Immunoprecipitation, Amino Acid Sequence, Cyclic AMP Response Element-Binding Protein, Promoter Regions, Genetic, Molecular Biology, Gene, Transcription factor, In Situ Hybridization, Oligonucleotide Array Sequence Analysis, Neurons, biology, Ccaat-enhancer-binding proteins, Cell Biology, Molecular biology, Nerve Regeneration, Rats, Repressor Proteins, Basic-Leucine Zipper Transcription Factors, Gene Expression Regulation, CCAAT-Enhancer-Binding Proteins, biology.protein, SDG 6 - Clean Water and Sanitation, Chromatin immunoprecipitation, Genome-Wide Association Study
Abstract

NFIL3 (nuclear factor IL-3 regulated) is a multifunctional transcription factor implicated in a wide range of physiological processes, including cellular survival, circadian gene expression and natural killer cell development. We recently demonstrated that NFIL3 acts as a repressor of CREB-induced gene expression underlying the regeneration of axotomized DRG sensory neurons. In this study we performed chromatin immunoprecipitation assays combined with microarray technology (ChIP-chip) to reveal direct NFIL3 and CREB target genes in an in vitro cell model for regenerating DRG neurons. We identified 505 promoter regions bound by NFIL3 and 924 promoter regions bound by CREB. Based on promoter analysis of NFIL3-bound genes, we were able to redefine the NFIL3 consensus-binding motif. Histone H3 acetylation profiling and gene expression microarray analysis subsequently indicated that a large fraction (> 60%) of NFIL3 target genes were transcriptionally silent, whereas CREB target genes in general were transcriptionally active. Only a small subset of NFIL3 target genes also bound CREB. Computational analysis indicated that a substantial number of NFIL3 target genes share a C/EBP (CCAAT/Enhancer Binding Protein) DNA binding motif. ChIP analysis confirmed binding of C/EBPs to NFIL3 target genes, and knockdown of C/EBPα, C/EBPβ and C/EBPδ, but not C/EBPγ, significantly reduced neurite outgrowth in vitro. Together, our findings show that NFIL3 is a general feed-forward repressor of basic leucine zipper transcription factors that control neurite outgrowth. © 2010 Elsevier Inc.

Published
2011
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