Receptor for advanced glycation end products (RAGE) mediates neuronal differentiation and neurite outgrowth
Lingyan Wang
Department of Neurobiology, E. K. Shriver Center, University of Massachusetts Medical School, Waltham, Massachusetts
Search for more papers by this authorShitao Li
Department of Pathology, Harvard Medical School, Boston, Massachusetts
Search for more papers by this authorCorresponding Author
Firoze B. Jungalwala
Department of Neurobiology, E. K. Shriver Center, University of Massachusetts Medical School, Waltham, Massachusetts
Department of Neurobiology, E. K. Shriver Center at University of Massachusetts Medical School, 200 Trapelo Road, Waltham, MA 02452Search for more papers by this authorLingyan Wang
Department of Neurobiology, E. K. Shriver Center, University of Massachusetts Medical School, Waltham, Massachusetts
Search for more papers by this authorShitao Li
Department of Pathology, Harvard Medical School, Boston, Massachusetts
Search for more papers by this authorCorresponding Author
Firoze B. Jungalwala
Department of Neurobiology, E. K. Shriver Center, University of Massachusetts Medical School, Waltham, Massachusetts
Department of Neurobiology, E. K. Shriver Center at University of Massachusetts Medical School, 200 Trapelo Road, Waltham, MA 02452Search for more papers by this authorAbstract
The receptor for advanced glycation end products (RAGE) plays a crucial role in several disease processes, such as diabetes, inflammation, and neurodegeneration. In this article we report multiple roles of RAGE in neuronal differentiation and neurite outgrowth. In retinoic-induced P19 embryonic carcinoma stem cells, silencing the expression of RAGE by RNA interference (RNAi) blocked differentiation of the P19 cells into neuronal cells and enhanced the formation of vimentin-positive fibroblast-like cells. RAGE knockdown inhibited retinoic acid–induced activation and blocked nuclear translocation of NF-κB, suggesting RAGE regulates activation of NF-κB. RAGE was also shown to be involved in survival of P19 cells during retinoic acid differentiation. Additionally, knockdown of RAGE strongly inhibited neurite outgrowth in retinoic acid–differentiated P19 cells, indicating that RAGE is required for neurite outgrowth of differentiated P19 cells. Retinoic acid–treated P19 cells activated GTPases, Rac1, and Cdc42. This activation of the GTPases was inhibited in RAGE-knockdown cells. In primary cerebellar granule neurons, the knockdown of RAGE also inhibited neurite outgrowth. In these cells, overexpression of dominant-negative forms of Rac1 and Cdc42 inhibited neurite outgrowth, whereas overexpression of constitutively active forms of Rac1 and Cdc42 in RAGE-deficient neurons restored neurite outgrowth, indicating that RAGE mediated neurite outgrowth through the Rac1/Cdc42 pathway. This is the first report on the role of RAGE in cell lines and primary neurons, as determined by RNAi knockdown. © 2007 Wiley-Liss, Inc.
REFERENCES
- Bain G,Yao M,Huettner JE,Finley FA,Gottlieb DI. 1998. Neuronlike cells derived in cultures from P 19 embryonal carcinoma and embryonic stem cells. In: G Banker, K Goslin, editors. Culturing Nerve Cells. 2nd ed. Cambridge, MA: MIT Press.
- Bierhaus A,Haslbeck KM,Humpert PM,Liliensiek B,Dehmer T,Morcos M,Sayed AA,Andrassy M,Schiekofer S,Schneider JG,Schulz JB,Heuss D,Neundorfer B,Dierl S,Huber J,Tritschler H,Schmidt AM,Schwaninger M,Haering HU,Schleicher E,Kasper M,Stern DM,Arnold B,Nawroth PP. 2004. Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J Clin Invest 114: 1741–1751.
- Bustin M. 1999. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins [review]. Mol Cell Biol 19: 5237–5246.
- Capela A,Temple S. 2002. LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35: 865–875.
- Chou DK,Henion TR,Jungalwala FB. 2003. Regulation of expression of sulfoglucuronyl carbohydrate HNK-1, Amphoterin and RAGE in retinoic acid-differentiated P19 embryonal carcinoma cells. J Neurochem 86: 917–931.
- Chou DK,Jungalwala FB. 1996. N-acetylglucosaminyl transferase regulates the expression of the sulfoglucuronyl glycolipids in specific cell types in cerebellum during development. J Biol Chem 271: 28868–26874.
- Chou DK,Zhang J,Smith FI,McCaffery P,Jungalwala FB. 2004. Developmental expression of receptor for advanced glycation end products (RAGE), amphoterin and sulfoglucuronyl (HNK-1) carbohydrate in mouse cerebellum and their role in neurite outgrowth and cell migration. J Neurochem 90: 1389–1401
- Constien R,Forde A,Liliensiek B,Grone HJ,Nawroth P,Hammerling G,Arnold B. 2001. Characterization of a novel EGFP reporter mouse to monitor Cre recombination as demonstrated by a Tie2 Cre mouse line. Genesis 30: 36–44
- Ding Q,Keller JN. 2005. Evaluation of rage isoforms, ligands, and signaling in the brain [review]. Biochim Biophys Acta 1746: 18–27.
- Donato R. 2001. S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles [review]. Int J Biochem Cell Biol 33: 637–668.
- DuYan S,Zhu H,Fu J,Yan SF,Roher A,Tourtellotte WW,Rajavashisth T,Chen X,Godman GC,Stern D,Schmidt AM. 1997. Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. Proc Natl Acad Sci U S A 94: 5296–5301
- Fages C,Nolo R,Huttunen HJ,Eskelinen E,Rauvala H. 2000. Regulation of cell migration by amphoterin. J Cell Sci 113: 611–620
- Farina AR,Masciulli MP,Tacconelli A,Cappabianca L,De Santis G,Gulino A,Mackay AR. 2002. All-trans-retinoic acid induces nuclear factor B activation and matrix metalloproteinase-9 expression and enhances basement membrane invasivity of differentiation-resistant human SK-N-BE 9N neuroblastoma cells. Cell Growth Differ 13: 343–354
- Feng Z,Porter AG. 1999. NF-B/Rel proteins are required for neuronal differentiation of SH-SY5Y neuroblastoma cells. J Biol Chem 274: 30341–30344.
- Fridmacher V,Kaltschmidt B,Goudeau B,Ndiaye D,Rossi FM,Pfeiffer J,Kaltschmidt C,Israel A,Memet S. 2003. Forebrain-specific neuronal inhibition of nuclear factor-kappaB activity leads to loss of neuroprotection. J Neurosci 23: 9403–9408.
- Gotz M,Stoykova A,Gruss P. 1998. Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21: 1031–1044.
- Guerrini L,Blasi F,Denis-Donini S. 1995. Synaptic activation of NF-kappa B by glutamate in cerebellar granule neurons in vitro. Proc Natl Acad Sci U S A 92: 9077–9081.
- Hatten ME. 1985. Neuronal regulation of astroglial morphology and proliferation in vitro. J Cell Biol 100: 384–396.
- Hofmann MA,Drury S,Fu C,Qu W,Taguchi A,Lu Y,Avila C,Kambham N,Bierhaus A,Nawroth P,Neurath MF,Slattery T,Beach D,McClary J,Nagashima M,Morser J,Stern D,Schmidt AM. 1999. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97: 889–901.
- Hori O,Brett J,Slattery T,Cao R,Zhang J,Chen JX,Nagashima M.,Lundh ER,Vijay S,Nitecki D,Morser J,Stern D,Schmidt AM. 1995. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. JBiol Chem 270: 25752–25761.
- Huttunen HJ,Fages C,Rauvala H. 1999. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 274: 19919–19924.
- Huttunen HJ,Kuja-Panula J,Sorci G,Agneletti AL,Donato R,Rauvala H. 2000. Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem 275: 40096–40105
- Huttunen HJ,Kuja-Panula J,Rauvala H. 2002. Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation. J Biol Chem 277: 38635–38646.
- Huttunen HJ,Rauvala H. 2004. Amphoterin as an extracellular regulator of cell motility: from discovery to disease [review]. J Intern Med 255: 351–366.
- Jones-Villeneuve EM,McBurney MW,Rogers KA,Kalnins VI. 1982. Retinoic acid induces embryonal carcinoma cells to differentiate into neurons and glial cells. J Cell Biol 94: 253–262.
- Kaltschmidt C,Kaltschmidt B,Baeuerle PA. 1995. Stimulation of ionotropic glutamate receptors activates transcription factor NF-kappa B in primary neurons. Proc Natl Acad Sci U S A 92: 9618–9622.
- Lander HM,Tauras JM,Ogiste JS,Hori O,Moss RA,Schmidt AM. 1997. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272: 17810–17814.
- Liliensiek B,Weigand MA,Bierhaus A,Nicklas W,Kasper M,Hofer S,Plachky J,Grone HJ,Kurschus FC,Schmidt AM,Yan SD,Martin E,Schleicher E,Stern DM,Hammerling GG,Nawroth PP,Arnold B. 2004. Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Invest 113: 1641–1650.
- Li ST,Wang LY,Berman MA,Zhang Y,Dorf ME. 2006. RNA screen in mouse astrocytes identifies phosphatases that regulate NF-kappa B signaling. Mol Cell 24: 497–509.
- Luo L. 2000. Rho GTPases in neuronal morphogenesis [review]. Nat Rev Neurosci 1: 173–180.
- Mattson MP. 2004. Pathways towards and away from Alzheimer's disease [review]. Nature 430: 631–639.
- Mattson MP,Camandola S. 2001. NF-kappaB in neuronal plasticity and neurodegenerative disorders [review]. J Clin Invest 107: 247–254.
- Meffert MK,Chang JM,Wiltgen BJ,Fanselow MS,Baltimore D. 2003. NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci. 6: 1072–1078.
- Melino G,Thiele CJ,Knight RA,Piacentini M. 1997. Retinoids and the control of growth/death decisions in human neuroblastoma cell lines [review]. J Neurooncol 31: 65–83.
- Merlo E,Freudenthal R,Romano A. 2002. The IkappaB kinase inhibitor sulfasalazine impairs long-term memory in the crab Chasmagnathus. Neuroscience 112: 161–172.
- Neeper M,Schmidt AM,Brett J,Yan SD,Wang F,Pan YC,Elliston K,Stern D,Shaw A. 1992. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267: 14998–15004.
- Nikolic M. 2002. The role of Rho GTPases and associated kinases in regulating neurite outgrowth [review]. Int J Biochem Cell Biol 34: 731–745.
- Nobes CD,Hall A. 1995. Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia and filopodia. Cell 81: 53–62
- Okamoto K,Okazawa H,Okuda A,Sakai M,Muramatsu M,Hamada H. 1990. A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 60: 461–472.
- O'Neill LA,Kaltschmidt C. 1997. NF-kappa B: a crucial transcription factor for glial and neuronal cell function [review]. Trends Neurosci 20: 252–258.
- Ramasamy R,Vannucci SJ,Yan SS,Herold K,Yan SF,Schmidt AM. 2005. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation [review]. Glycobiology 15: 16R–28R.
- Ridley AJ,Paterson HF,Johnston CL,Diekmann D,Hall A. 1992. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70: 401–410.
- Rong LL,Trojaborg W,Qu W,Kostov K,Yan SD,Gooch C,Szabolcs M,Hays AP,Schmidt AM. 2004a. Antagonism of RAGE suppresses peripheral nerve regeneration. FASEB J 18: 1812–1817.
- Rong LL,Yan SF,Wendt T,Hans D,Pachydaki S,Bucciarelli LG,Adebayo A,Qu W,Lu Y,Kostov K,Lalla E,Yan SD,Gooch C,Szabolcs M,Trojaborg W,Hays AP,Schmidt AM. 2004b. RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways. FASEB J 18: 1818–1825.
- Sajithlal G,Huttunen H,Rauvala H,Munch G. 2002. Receptor for advanced glycation end products plays a more important role in cellular survival than in neurite outgrowth during retinoic acid-induced differentiation of neuroblastoma cells. J Biol Chem 277: 6888–6897.
- Sakaguchi T,Yan SF,Yan SD,Belov D,Rong LL,Sousa M,Andrassy M,Marso SP,Duda S,Arnold B,Liliensiek B,Nawroth PP,Stern DM,Schmidt AM,Naka Y. 2003. Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Invest 111: 959–972.
- Schmidt AM,Hori O,Cao R,Yan SD,Brett J,Wautier JL,Ogawa S,Kuwabara K,Matsumoto M,Stern D. 1996. RAGE: a novel cellular receptor for advanced glycation end products [review]. Diabetes 45: S77–S80.
- Schmidt AM,Vianna M,Gerlach M,Brett J,Ryan J,Kao J,Esposito C,Hegarty H,Hurley W,Clauss M, et al. 1992. Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. JBiol Chem 267: 14987–14997.
- Schmidt AM,Yan SD,Yan SF,Stern DM. 2000. The biology of the receptor for advanced glycation end products and its ligands [review]. Biochim Biophys Acta 1498: 99–111.
- Schoorlemmer J,Jonk L,Sanbing S,van Puijenbroek A,Feijen A,Kruijer W. 1995. Regulation of Oct-4 gene expression during differentiation of EC cells. Mol Biol Rep 21: 129–140.
- Stoykova A,Gruss P. 1994. Roles of Pax-genes in developing and adult brain as suggested by expression patterns. J Neurosci 14: 1395–1412.
- Taguchi A,Blood DC,del Toro G,Canet A,Lee DC,Qu W,Tanji N,Lu Y,Lalla E,Fu C,Hofmann MA,Kislinger T,Ingram M,Lu A,Tanaka H,Hori O,Ogawa S,Stern DM,Schmidt AM. 2000. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405: 354–360.
- Yamamoto Y,Kato I,Doi T,Yonekura H,Ohashi S,Takeuchi M,Watanabe T,Yamagishi S,Sakurai S,Takasawa S,Okamoto H,Yamamoto H. 2001. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Invest 108: 261–268
- Yan SD,Chen X,Fu J,Chen M,Zhu H,Roher A,Slattery T,Zhao L,Nagashima M,Morser J,Migheli A,Nawroth P,Stern D,Schmidt AM. 1996. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 382: 685–691.
- Yan SD,Schmidt AM,Anderson GM,Zhang J,Brett J,Zou YS,Pinsky D,Stern D. 1994. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 269: 9889–9897.
- Zhao Z,Chou DK,Nair SM,Tobet S,Jungalwala FB. 2000a. Expression of sulfoglucuronyl (HNK-1) carbohydrate and its binding protein (SBP-1) in developing rat cerebellum. Brain Res Dev Brain Res 120: 165–180.
- Zhao Z,Nair SM,Chou DK,Tobet SA,Jungalwala FB. 2000b. Expression and role of sulfoglucuronyl (HNK-1) carbohydrate and its binding protein SBP-1 in developing rat cerebral cortex. J Neurosci Res 62: 186–205.