Anatomy and Cell Biology

Korean Association of Anatomists (대한해부학회)
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Co-localization of activating transcription factor 3 and phosphorylated c-Jun in axotomized facial motoneurons

  • Park, Byung-Gu (Department of Anatomy, Yonsei University Wonju College of Medicine) ;
  • Lee, Jin-Sook (Department of Anatomy, Yonsei University Wonju College of Medicine) ;
  • Lee, Ji-Yong (Department of Anatomy, Yonsei University Wonju College of Medicine) ;
  • Song, Dae-Yong (Department of Anatomy and Neuroscience, Eulji University School of Medicine) ;
  • Jeong, Seong-Woo (Department of Physiology, Yonsei University Wonju College of Medicine) ;
  • Cho, Byung-Pil (Department of Anatomy, Yonsei University Wonju College of Medicine)
  • Published : 2011.09.30
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Abstract

Activating transcription factor 3 (ATF3) and c-Jun play key roles in either cell death or cell survival, depending on the cellular background. To evaluate the functional significance of ATF3/c-Jun in the peripheral nervous system, we examined neuronal cell death, activation of ATF3/c-Jun, and microglial responses in facial motor nuclei up to 24 weeks after an extracranial facial nerve axotomy in adult rats. Following the axotomy, neuronal survival rate was progressively but significantly reduced to 79.1% at 16 weeks post-lesion (wpl) and to 65.2% at 24 wpl. ATF3 and phosphorylated c-Jun (pc-Jun) were detected in the majority of ipsilateral facial motoneurons with normal size and morphology during the early stage of degeneration (1-2 wpl). Thereafter, the number of facial motoneurons decreased gradually, and both ATF3 and pc-Jun were identified in degenerating neurons only. ATF3 and pc-Jun were co-localized in most cases. Additionally, a large number of activated microglia, recognized by OX6 (rat MHC II marker) and ED1 (phagocytic marker), gathered in the ipsilateral facial motor nuclei. Importantly, numerous OX6- and ED1-positive, phagocytic microglia closely surrounded and ingested pc-Jun-positive, degenerating neurons. Taken together, our results indicate that long-lasting co-localization of ATF3 and pc-Jun in axotomized facial motoneurons may be related to degenerative cascades provoked by an extracranial facial nerve axotomy.

Keywords

References

  1. Haas CA, Donath C, Kreutzberg GW. Differential expression of immediate early genes after transection of the facial nerve. Neuroscience 1993;53:91-9. https://doi.org/10.1016/0306-4522(93)90287-P
  2. Sheng M, Greenberg ME. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 1990;4:477-85.
  3. Herdegen T, Skene P, Bähr M. The c-Jun transcription factor: bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci 1997;20:227-31. https://doi.org/10.1016/S0166-2236(96)01000-4
  4. Song DY, Yang YC, Shin DH, Sugama S, Kim YS, Lee BH, Joh TH, Cho BP. Axotomy-induced dopaminergic neurodegeneration is accompanied with c-Jun phosphorylation and activation transcription factor 3 expression. Exp Neurol 2008;209:268-78. https://doi.org/10.1016/j.expneurol.2007.09.033
  5. Tsujino H, Kondo E, Fukuoka T, Dai Y, Tokunaga A, Miki K, Yonenobu K, Ochi T, Noguchi K. Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: a novel neuronal marker of nerve injury. Mol Cell Neurosci 2000;15:170-82. https://doi.org/10.1006/mcne.1999.0814
  6. Chen BP, Wolfgang CD, Hai T. Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10. Mol Cell Biol 1996;16:1157-68. https://doi.org/10.1128/MCB.16.3.1157
  7. Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U. ATF3 and stress responses. Gene Expr 1999;7:321-35.
  8. Kawauchi J, Zhang C, Nobori K, Hashimoto Y, Adachi MT, Noda A, Sunamori M, Kitajima S. Transcriptional repressor activating transcription factor 3 protects human umbilical vein endothelial cells from tumor necrosis factor-alpha-induced apoptosis through down-regulation of p53 transcription. J Biol Chem 2002;277:39025-34. https://doi.org/10.1074/jbc.M202974200
  9. Nakagomi S, Suzuki Y, Namikawa K, Kiryu-Seo S, Kiyama H. Expression of the activating transcription factor 3 prevents c-Jun N-terminal kinase-induced neuronal death by promoting heat shock protein 27 expression and Akt activation. J Neurosci 2003;23:5187-96.
  10. Hartman MG, Lu D, Kim ML, Kociba GJ, Shukri T, Buteau J, Wang X, Frankel WL, Guttridge D, Prentki M, Grey ST, Ron D, Hai T. Role for activating transcription factor 3 in stress-induced beta-cell apoptosis. Mol Cell Biol 2004;24:5721-32. https://doi.org/10.1128/MCB.24.13.5721-5732.2004
  11. Mashima T, Udagawa S, Tsuruo T. Involvement of transcriptional repressor ATF3 in acceleration of caspase protease activation during DNA damaging agent-induced apoptosis. J Cell Physiol 2001;188:352-8. https://doi.org/10.1002/jcp.1130
  12. Hai T, Curran T. Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A 1991;88:3720-4. https://doi.org/10.1073/pnas.88.9.3720
  13. Leah JD, Herdegen T, Bravo R. Selective expression of Jun proteins following axotomy and axonal transport block in peripheral nerves in the rat: evidence for a role in the regeneration process. Brain Res 1991;566:198-207. https://doi.org/10.1016/0006-8993(91)91699-2
  14. Sommer C, Gass P, Kiessling M. Selective c-JUN expression in CA1 neurons of the gerbil hippocampus during and after acquisition of an ischemia-tolerant state. Brain Pathol 1995;5:135-44. https://doi.org/10.1111/j.1750-3639.1995.tb00587.x
  15. Dragunow M, Beilharz E, Sirimanne E, Lawlor P, Williams C, Bravo R, Gluckman P. Immediate-early gene protein expression in neurons undergoing delayed death, but not necrosis, following hypoxic-ischaemic injury to the young rat brain. Brain Res Mol Brain Res 1994;25:19-33. https://doi.org/10.1016/0169-328X(94)90274-7
  16. Dragunow M, Young D, Hughes P, MacGibbon G, Lawlor P, Singleton K, Sirimanne E, Beilharz E, Gluckman P. Is c-Jun involved in nerve cell death following status epilepticus and hypoxic-ischaemic brain injury? Brain Res Mol Brain Res 1993;18:347-52. https://doi.org/10.1016/0169-328X(93)90101-T
  17. Ferrer I, Olive M, Ribera J, Planas AM. Naturally occurring (programmed) and radiation-induced apoptosis are associated with selective c-Jun expression in the developing rat brain. Eur J Neurosci 1996;8:1286-98. https://doi.org/10.1111/j.1460-9568.1996.tb01297.x
  18. Oo TF, Henchcliffe C, James D, Burke RE. Expression of c-fos, c-jun, and c-jun N-terminal kinase (JNK) in a developmental model of induced apoptotic death in neurons of the substantia nigra. J Neurochem 1999;72:557-64. https://doi.org/10.1046/j.1471-4159.1999.0720557.x
  19. Crocker SJ, Lamba WR, Smith PD, Callaghan SM, Slack RS, Anisman H, Park DS. c-Jun mediates axotomy-induced dopamine neuron death in vivo. Proc Natl Acad Sci U S A 2001;98:13385-90. https://doi.org/10.1073/pnas.231177098
  20. Anderson AJ, Cummings BJ, Cotman CW. Increased immunoreactivity for Jun- and Fos-related proteins in Alzheimer's disease: association with pathology. Exp Neurol 1994;125:286-95. https://doi.org/10.1006/exnr.1994.1031
  21. Martin G, Segui J, Diaz-Villoslada P, Montalban X, Planas AM, Ferrer I. Jun expression is found in neurons located in the vicinity of subacute plaques in patients with multiple sclerosis. Neurosci Lett 1996;212:95-8. https://doi.org/10.1016/0304-3940(96)12776-2
  22. Cho BP, Song DY, Sugama S, Shin DH, Shimizu Y, Kim SS, Kim YS, Joh TH. Pathological dynamics of activated microglia following medial forebrain bundle transection. Glia 2006;53:92-102. https://doi.org/10.1002/glia.20265
  23. Cho BP, Sugama S, Shin DH, DeGiorgio LA, Kim SS, Kim YS, Lim SY, Park KC, Volpe BT, Cho S, Joh TH. Microglial phagocytosis of dopamine neurons at early phases of apoptosis. Cell Mol Neurobiol 2003;23:551-60. https://doi.org/10.1023/A:1025024129946
  24. Sugama S, Cho BP, Degiorgio LA, Shimizu Y, Kim SS, Kim YS, Shin DH, Volpe BT, Reis DJ, Cho S, Joh TH. Temporal and sequential analysis of microglia in the substantia nigra following medial forebrain bundle axotomy in rat. Neuroscience 2003;116:925-33. https://doi.org/10.1016/S0306-4522(02)00572-9
  25. Takeda M, Kato H, Takamiya A, Yoshida A, Kiyama H. Injuryspecific expression of activating transcription factor-3 in retinal ganglion cells and its colocalized expression with phosphorylated c-Jun. Invest Ophthalmol Vis Sci 2000;41:2412-21.
  26. Guntinas-Lichius O, Neiss WF, Gunkel A, Stennert E. Differences in glial, synaptic and motoneuron responses in the facial nucleus of the rat brainstem following facial nerve resection and nerve suture reanastomosis. Eur Arch Otorhinolaryngol 1994;251:410-7.
  27. Johnson IP, Duberley RM. Motoneuron survival and expression of neuropeptides and neurotrophic factor receptors following axotomy in adult and ageing rats. Neuroscience 1998;84:141-50. https://doi.org/10.1016/S0306-4522(97)00500-9
  28. Mattsson P, Meijer B, Svensson M. Extensive neuronal cell death following intracranial transection of the facial nerve in the adult rat. Brain Res Bull 1999;49:333-41. https://doi.org/10.1016/S0361-9230(98)00178-6
  29. Gehrmann J, Mies G, Bonnekoh P, Banati R, Iijima T, Kreutzberg GW, Hossmann KA. Microglial reaction in the rat cerebral cortex induced by cortical spreading depression. Brain Pathol 1993;3:11-7. https://doi.org/10.1111/j.1750-3639.1993.tb00720.x
  30. Graeber MB, Lopez-Redondo F, Ikoma E, Ishikawa M, Imai Y, Nakajima K, Kreutzberg GW, Kohsaka S. The microglia/macrophage response in the neonatal rat facial nucleus following axotomy. Brain Res 1998;813:241-53. https://doi.org/10.1016/S0006-8993(98)00859-2
  31. Graeber MB, Streit WJ, Kreutzberg GW. Axotomy of the rat facial nerve leads to increased CR3 complement receptor expression by activated microglial cells. J Neurosci Res 1988;21:18-24. https://doi.org/10.1002/jnr.490210104
  32. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 4th ed. San Diego: Academic Press; 1998.
  33. Damoiseaux JG, Dopp EA, Calame W, Chao D, MacPherson GG, Dijkstra CD. Rat macrophage lysosomal membrane antigen recognized by monoclonal antibody ED1. Immunology 1994;83:140-7.
  34. Streit WJ, Kreutzberg GW. Response of endogenous glial cells to motor neuron degeneration induced by toxic ricin. J Comp Neurol 1988;268:248-63. https://doi.org/10.1002/cne.902680209
  35. Dragunow M, Preston K. The role of inducible transcription factors in apoptotic nerve cell death. Brain Res Brain Res Rev 1995;21:1-28. https://doi.org/10.1016/0165-0173(95)00003-L
  36. Barron KD. The axotomy response. J Neurol Sci 2004;220:119-21. https://doi.org/10.1016/j.jns.2004.03.009
  37. Lindwall C, Kanje M. Retrograde axonal transport of JNK signaling molecules influence injury induced nuclear changes in p-c-Jun and ATF3 in adult rat sensory neurons. Mol Cell Neurosci 2005;29:269-82. https://doi.org/10.1016/j.mcn.2005.03.002
  38. Raivich G, Bohatschek M, Da Costa C, Iwata O, Galiano M, Hristova M, Nateri AS, Makwana M, Riera-Sans L, Wolfer DP, Lipp HP, Aguzzi A, Wagner EF, Behrens A. The AP-1 transcription factor c-Jun is required for efficient axonal regeneration. Neuron 2004;43:57-67. https://doi.org/10.1016/j.neuron.2004.06.005
  39. Brecht S, Kirchhof R, Chromik A, Willesen M, Nicolaus T, Raivich G, Wessig J, Waetzig V, Goetz M, Claussen M, Pearse D, Kuan CY, Vaudano E, Behrens A, Wagner E, Flavell RA, Davis RJ, Herdegen T. Specific pathophysiological functions of JNK isoforms in the brain. Eur J Neurosci 2005;21:363-77. https://doi.org/10.1111/j.1460-9568.2005.03857.x
  40. Pittman RN, Messam CA, Mills JC. Asynchronous death as a characteristics feature of apoptosis. In: Koliatsos VE, Ratan RR, editors. Cell Death and Diseases of the Nervous System. Totowa: Hamana Press; 1998. p.29-44.
  41. Reimold AM, Grusby MJ, Kosaras B, Fries JW, Mori R, Maniwa S, Clauss IM, Collins T, Sidman RL, Glimcher MJ, Glimcher LH. Chondrodysplasia and neurological abnormalities in ATF-2-deficient mice. Nature 1996;379:262-5. https://doi.org/10.1038/379262a0
  42. Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol 1997;9:240-6. https://doi.org/10.1016/S0955-0674(97)80068-3

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