A transcriptional role for C/EBP beta in the neuronal response to axonal injury.
The molecular mechanisms responsible for inducing gene expression following neuronal injury are not well understood. Here, we address this issue by focusing upon C/EBPbeta, a transcription factor implicated in cellular injury and regeneration. We show that C/EBPbeta mRNA is expressed in neurons throughout the mature brain and that levels of both C/EBPbeta mRNA and phosphoprotein are increased in facial motor neurons following axonal injury. To determine the importance of these increases, we examined the regeneration-associated Talpha1 alpha-tubulin gene which contains functional C/EBP binding sites in its promoter. In transgenic mice, expression of a minimal 176 nucleotide Talpha1 alpha-tubulin promoter:nlacZ reporter gene was upregulated in injured facial motor neurons. This injury-induced transcriptional increase was inhibited in C/EBPbeta -/- mice. A similar inhibition was observed in C/EBPbeta -/- mice that carried a larger 1.1-kb promoter Talpha1:nlacZ reporter construct. Moreover, in situ hybridization revealed that the injury-induced upregulation of the endogenous mouse alpha1 alpha-tubulin mRNA, and of a second regeneration-associated mRNA, GAP-43, was inhibited in C/EBPbeta -/- mice. Thus, C/EBPbeta is essential for the neuronal injury response, acting to transcriptionally activate regeneration-associated gene expression.
Nadeau
Sylvain
S
Developmental Biology and Neurobiology and Behavior, Hospital for Sick Children, 3203 Black Wing, Toronto, Ontario, Canada M5G 1X5.
Hein
Paul
P
Fernandes
Karl J L
KJ
Peterson
Alan C
AC
Miller
Freda D
FD
D000818:Animals; D001369:Axons / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000378:metabolism; D020220:Facial Nerve Injuries / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D019922:GAP-43 Protein / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism*; D009416:Nerve Regeneration / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D012183:Retrograde Degeneration / Q000378:metabolism* / Q000503:physiopathology; D015533:Transcriptional Activation / Q000235:genetics; D014404:Tubulin / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D022782:CCAAT-Enhancer-Binding Protein-beta; D019922:GAP-43 Protein; D010750:Phosphoproteins; D012333:RNA, Messenger; D014404:Tubulin