Abstract
Nur77, together with Nurr1 and NOR-1, constitutes the NR4A subgroup of orphan nuclear receptors and plays critical roles in cell proliferation, differentiation, migration, and apoptosis. Among them, Nur77 is universally well known to contribute to neurite outgrowth. However, information regarding its regulation and possible function in the peripheral nervous system is still limited. In this study, we performed a sciatic nerve injury model in adult rats and detected an increased expression of Nur77 in the sciatic nerve, which was similar to the expression of Oct-6. Immunofluorescence indicated that Nur77 was located in both axons and Schwann cells. In vitro, we observed enhanced expression of Nur77 during the process of both basic fibroblast growth factor (bFGF)-induced Schwann cells differentiation and nerve growth factor (NGF)-induced PC12 cell neurite outgrowth. In vitro and in vivo experiments indicated that inhibiting the function of Nur77 by specific short hairpin RNA could depress Schwann cells myelinization and axons regeneration. Collectively, all these results suggested that upregulation of Nur77 might be involved in Schwann cells differentiation and neurite elongation following sciatic nerve crush.
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Allodi I, Mecollari V, Gonzalez-Perez F, Eggers R, Hoyng S, Verhaagen J, Navarro X, Udina E (2014) Schwann cells transduced with a lentiviral vector encoding Fgf-2 promote motor neuron regeneration following sciatic nerve injury. Glia 62:1736–1746
Avellino AM, Hart D, Dailey AT, MacKinnon M, Ellegala D, Kliot M (1995) Differential macrophage responses in the peripheral and central nervous system during Wallerian degeneration of axons. Exp Neurol 136:183–198
Backman C, Perlmann T, Wallen A, Hoffer BJ, Morales M (1999) A selective group of dopaminergic neurons express Nurr1 in the adult mouse brain. Brain Res 851:125–132
Baron O, Forthmann B, Lee YW, Terranova C, Ratzka A, Stachowiak EK, Grothe C, Claus P, Stachowiak MK (2012) Cooperation of nuclear fibroblast growth factor receptor 1 and Nurr1 offers new interactive mechanism in postmitotic development of mesencephalic dopaminergic neurons. J Biol Chem 287:19827–19840
Boldingh Debernard KA, Mathisen GH, Paulsen RE (2012) Differences in NGFI-B, Nurr1, and NOR-1 expression and nucleocytoplasmic translocation in glutamate-treated neurons. Neurochem Int 61:79–88
Brosius Lutz A, Barres BA (2014) Contrasting the glial response to axon injury in the central and peripheral nervous systems. Dev Cell 28:7–17
Camara-Lemarroy CR, Guzman-de la Garza FJ, Fernandez-Garza NE (2010) Molecular inflammatory mediators in peripheral nerve degeneration and regeneration. Neuroimmunomodulation 17:314–324
Cao L, Zhu YL, Su Z, Lv B, Huang Z, Mu L, He C (2007) Olfactory ensheathing cells promote migration of Schwann cells by secreted nerve growth factor. Glia 55:897–904
Castillo SO, Baffi JS, Palkovits M, Goldstein DS, Kopin IJ, Witta J, Magnuson MA, Nikodem VM (1998) Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene. Mol Cell Neurosci 11:36–46
Chen ZL, Yu WM, Strickland S (2007) Peripheral regeneration. Annu Rev Neurosci 30:209–233
Dragunow M, Abraham W, Hughes P (1996) Activation of NMDA and muscarinic receptors induces nur-77 mRNA in hippocampal neurons. Brain Res Mol Brain Res 36:349–356
Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49:377–391
Fu SY, Gordon T (1997) The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 14:67–116
Gubits RM, Burke RE, Casey-McIntosh G, Bandele A, Munell F (1993) Immediate early gene induction after neonatal hypoxia-ischemia. Brain Res Mol Brain Res 18:228–238
Hashida R, Ohkura N, Saito H, Tsujimoto G (2007) The NR4A nuclear receptor family in eosinophils. J Hum Genet 52:13–20
Hawk JD, Abel T (2011) The role of NR4A transcription factors in memory formation. Brain Res Bull 85:21–29
Hermann GE, Rogers RC, Bresnahan JC, Beattie MS (2001) Tumor necrosis factor-alpha induces cFOS and strongly potentiates glutamate-mediated cell death in the rat spinal cord. Neurobiol Dis 8:590–599
Koep LJ, Konigsmark BW, Sperber EE (1970) Cellular changes in the human supraoptic and paraventricular hypothalamic nuclei in dehydration. J Neuropathol Exp Neurol 29:254–265
Kury P, Stoll G, Muller HW (2001) Molecular mechanisms of cellular interactions in peripheral nerve regeneration. Curr Opin Neurol 14:635–639
Landry ES, Rouillard C, Levesque D, Guertin PA (2006) Profile of immediate early gene expression in the lumbar spinal cord of low-thoracic paraplegic mice. Behav Neurosci 120:1384–1388
Le W, Conneely OM, Zou L, He Y, Saucedo-Cardenas O, Jankovic J, Mosier DR, Appel SH (1999) Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice. Exp Neurol 159:451–458
Lee YW, Terranova C, Birkaya B, Narla S, Kehoe D, Parikh A, Dong S, Ratzka A, Brinkmann H, Aletta JM, Tzanakakis ES, Stachowiak EK, Claus P, Stachowiak MK (2012) A novel nuclear FGF receptor-1 partnership with retinoid and Nur receptors during developmental gene programming of embryonic stem cells. J Cell Biochem 113:2920–2936
Lee YW, Stachowiak EK, Birkaya B, Terranova C, Capacchietti M, Claus P, Aletta JM, Stachowiak MK (2013) NGF-induced cell differentiation and gene activation is mediated by integrative nuclear FGFR1 signaling (INFS). PLoS One 8, e68931
Lundborg G (2003) Richard P. Bunge memorial lecture. Nerve injury and repair—a challenge to the plastic brain. J Peripher Nerv Syst 8:209–226
Maruoka H, Sasaya H, Shimamura Y, Nakatani Y, Shimoke K, Ikeuchi T (2010) Dibutyryl-cAMP up-regulates nur77 expression via histone modification during neurite outgrowth in PC12 cells. J Biochem 148:93–101
Milbrandt J (1988) Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1:183–188
Noble J, Munro CA, Prasad VS, Midha R (1998) Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. J Trauma 45:116–122
Richner M, Ulrichsen M, Elmegaard SL, Dieu R, Pallesen LT, Vaegter CB (2014) Peripheral nerve injury modulates neurotrophin signaling in the peripheral and central nervous system. Mol Neurobiol 50:945–970
Robinson LR (2000) Traumatic injury to peripheral nerves. Muscle Nerve 23:863–873
Son YJ, Thompson WJ (1995) Schwann cell processes guide regeneration of peripheral axons. Neuron 14:125–132
Tannemaat MR, Eggers R, Hendriks WT, de Ruiter GC, van Heerikhuize JJ, Pool CW, Malessy MJ, Boer GJ, Verhaagen J (2008) Differential effects of lentiviral vector-mediated overexpression of nerve growth factor and glial cell line-derived neurotrophic factor on regenerating sensory and motor axons in the transected peripheral nerve. Eur J Neurosci 28:1467–1479
Woronicz JD, Calnan B, Ngo V, Winoto A (1994) Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367:277–281
Yan M, Cheng C, Shao X, Qian J, Shen A, Xia C (2008) Expression change of beta-1,4 galactosyltransferase I, V mRNAs and Galbeta1,4GlcNAc group in rat sciatic nerve after crush. J Mol Histol 39:317–328
Yu X, Wen H, Cao J, Sun B, Ding T, Li M, Wu H, Long L, Cheng X, Xu G, Zhang F (2013) Temporal and spatial expression of KIF3B after acute spinal cord injury in adult rats. J Mol Neurosci 49:387–394
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 81171140, No. 81471258), the Colleges and Universities in Natural Science Research Project of Jiangsu Province (No. 13KJB31009), and a project funded by the Priority Academic Program Development of jiangsu Higher Education Institution (PAPD).
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Weidong Zhang and Xudong Zhu contributed equally to this work.
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Zhang, W., Zhu, X., Liu, Y. et al. Nur77 Was Essential for Neurite Outgrowth and Involved in Schwann Cell Differentiation After Sciatic Nerve Injury. J Mol Neurosci 57, 38–47 (2015). https://doi.org/10.1007/s12031-015-0575-9
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DOI: https://doi.org/10.1007/s12031-015-0575-9