Noxa is a critical mediator of p53-dependent motor neuron death after nerve injury in adult mouse.
Axotomy-induced motor neuron death occurs within a week in the neonatal rat and mouse. However, slowly progressive motor neuron death, which takes more than a month, occurs after axotomy in the adult mouse (C57BL/6) but not in the adult rat (Wistar). Here we demonstrate that expression of a p53-inducible Bcl-2 homology domain 3 (BH3)-only protein, Noxa, is enhanced in axotomized neurons of the adult mouse but not in the adult rat. In p53-deficient mice, slowly progressive neuronal death was suppressed and accompanied by reduced Noxa expression after axotomy. However, a minor response of Noxa expression was still observed after axotomy in p53-deficient mice, suggesting that p53-independent Noxa expression occurs to a minor extent. Noxa-deficient mice were used to confirm the consequence of Noxa expression in nerve-injured mouse motor neurons. In Noxa-deficient mice, axotomy-induced motor neuron death was suppressed. Furthermore, among the BH3-only protein members examined, Noxa exhibited the most marked upregulation after axotomy in the mouse. In conclusion, motor neuron death seen in the adult mouse is mainly p53 dependent, and Noxa is a major executor for axotomy-induced motor neuron death in the adult mouse, as a mediator located downstream of p53.
Kiryu-Seo
Sumiko
S
Department of Anatomy and Neurobiology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
Hirayama
Teruhisa
T
Kato
Ryuichi
R
Kiyama
Hiroshi
H
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019771:Axotomy; D005786:Gene Expression Regulation; D061228:Hypoglossal Nerve Injuries; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000473:pathology*; D009416:Nerve Regeneration; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*; D014855:Wallerian Degeneration
C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53