Peripheral but not central axotomy induces changes in Janus kinases (JAK) and signal transducers and activators of transcription (STAT).
Nerve injury leads to the release of a number of cytokines which have been shown to play an important role in cellular activation after peripheral nerve injury. The members of the signal transducer and activator of transcription (STAT) gene family are the main mediators in the signal transduction pathway of cytokines. After phosphorylation, STAT proteins are transported into the nucleus and exhibit transcriptional activity. Following axotomy in rat regenerating facial and hypoglossal neurons, a transient increase of mRNA for JAK2, JAK3, STAT1, STAT3 and STAT5 was detected using in situ hybridization and semi-quantitative polymerase chain reaction (PCR). Of the investigated STAT molecules, only STAT3 protein was significantly increased. In addition, activation of STAT3 by phosphorylation on position Tyr705 and enhanced nuclear translocation was found within 3 h in neurons and after 1 day in astrocytes. Unexpectedly, STAT3 tyrosine phosphorylation was obvious for more than 3 months. In contrast, none of these changes was found in response to axotomy of non-regenerating Clarke's nucleus neurons, although all the investigated models express c-Jun and growth-associated protein-43 (GAP-43) in response to axonal injury. Increased expression of Janus kinase (JAK) and STAT molecules after peripheral nerve transection suggests changes in the responsiveness of the neurons to signalling molecules. STAT3 as a transcription factor, which is expressed early and is activated persistently until the time of reinnervation, might be involved in the switch from the physiological gene expression to an 'alternative program' activated only after peripheral nerve injury.
Schwaiger
F W
FW
Department of Neuromorphology, Max-Planck Institute of Neurobiology, D-82152 Martinsried, Germany. schwaige@neuro.mpg.de
Hager
G
G
Schmitt
A B
AB
Horvat
A
A
Hager
G
G
Streif
R
R
Spitzer
C
C
Gamal
S
S
Breuer
S
S
Brook
G A
GA
Nacimiento
W
W
Kreutzberg
G W
GW
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D019771:Axotomy; D050822:Cytokine Receptor gp130; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005154:Facial Nerve / Q000166:cytology / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D007002:Hypoglossal Nerve / Q000166:cytology / Q000502:physiology*; D017403:In Situ Hybridization; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008894:Milk Proteins; D009416:Nerve Regeneration / Q000502:physiology; D009474:Neurons / Q000201:enzymology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology
D015703:Antigens, CD; D017931:DNA Primers; D004268:DNA-Binding Proteins; C494201:Il6st protein, rat; C507936:Jak3 protein, rat; D008562:Membrane Glycoproteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D053616:Janus Kinase 3