Journal of Neuroimmune Pharmacology

, Volume 7, Issue 4, pp 725–730 | Cite as

Wnt/β-catenin and its Diverse Physiological Cell Signaling Pathways in Neurodegenerative and Neuropsychiatric Disorders



Wnt signaling is a fundamental pathway in embryogenesis which is evolutionary conserved from metazoans to humans. Much of our understanding of Wnt signaling events emerged from key developmental studies in drosophila, zebra fish, xenopus, and mice. Considerable data now exists on the role of Wnt signaling beyond these developmental processes and in particular its role in health and disease. The focus of this special issue is on Wnt/β-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders. This special issue is composed of six reviews and two original articles selected to highlight recent advances in the role of Wnt signaling in CNS embryonic development, in adult brain function, in neurodegenerative conditions such as Alzheimer’s disease, schizophrenia, NeuroAIDS, and in gliomas. The finding that β-catenin can translocate to the nucleus where it binds to TCF/LEF transcription factors to regulate target gene expression was a seminal observation that linked β-catenin/LEF to T cell development and differentiation. We also provide a nostalgic look on recent advances in role of Wnts in T cell development and maturation. These reviews highlight the extensive body of work in these thematic areas as well as identify knowledge gaps, where appropriate. Understanding Wnt function under healthy and diseased conditions may provide a therapeutic resource, albeit it a challenging one, in diseases where dysfunctional and/or diminished Wnt signaling is a prominent player in the disease process.


Wnt signaling β-catenin Neurodegenerative diseases T cell differentation NeuroAIDS 



This special issue was the brain child of Dr. Howard Gendelman, Editor-in Chief of the Journal of Neuroimmune Pharmacology. I thank him for entrusting me with this jewel and for his continued support throughout this process. I thank my colleagues who contributed to this special issue and provided outstanding reviews that will contribute to a scientific dialogue on the topics. I thank the reviewers who evaluated these articles for their invaluable comments and suggestions to improve the manuscripts. I thank Ms. Robin Taylor for her outstanding administrative assistance as the managing editor for the Journal of Neuroimmune Pharmacology and Mr. Kevin Tomlinson, research administrative assistant, Dept. Immunology/Microbiology, Rush University Medical Center, for his outstanding assistance with graphics. Funding is provided by the National Institutes of Health R01 NS060632, R03 DA 026723, R01 DA 033966, and PO1A1082971.

Conflict of interest

The author has no declaration of conflict of interest


  1. Al-Harthi L (2012) Interplay between Wnt/β-catenin signaling and HIV: Virologic and biologic consequences in the CNS. J NeuroImmune Pharm (this issue) Google Scholar
  2. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382:638–642PubMedCrossRefGoogle Scholar
  3. Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, Andrew D, Nathans J, Nusse R (1996) A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382:225–230PubMedCrossRefGoogle Scholar
  4. Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ (2010) Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol 190:1079–1091PubMedCrossRefGoogle Scholar
  5. Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW, Wei S, Hao W, Kilgore J, Williams NS, Roth MG, Amatruda JF, Chen C, Lum L (2009) Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5:100–107Google Scholar
  6. DeCarolis NA, Wharton KA Jr, Eisch AJ (2008) Which way does the Wnt blow? Exploring the duality of canonical Wnt signaling on cellular aging. Bioessays 30:102–106PubMedCrossRefGoogle Scholar
  7. Duan Y, Liao AP, Kuppireddi S, Ye Z, Ciancio MJ, Sun J (2007) beta-Catenin activity negatively regulates bacteria-induced inflammation. Lab Invest 87:613–624PubMedCrossRefGoogle Scholar
  8. Graham TA, Weaver C, Mao F, Kimelman D, Xu W (2000) Crystal structure of a beta-catenin/Tcf complex. Cell 103:885–896PubMedCrossRefGoogle Scholar
  9. Henderson LJ, Al-Harthi L (2011) Role of beta-catenin/TCF-4 signaling in HIV Replication and Pathogenesis: insights to informing novel Anti-HIV molecular therapeutics. J Neuroimmune Pharmacol 6:247–259PubMedCrossRefGoogle Scholar
  10. Inestrosa N, Montecinos-Oliva C, Marco F (2012) Wnt signaling: Role in Alzheimer Disease and Schizophrenia. J NeuroImmune Pharm (this issue) Google Scholar
  11. Jin T, Fantus IG, Sun J (2008) Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. Cell Signal 20:1697–1704PubMedCrossRefGoogle Scholar
  12. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science 275:1784–1787PubMedCrossRefGoogle Scholar
  13. Liu J, Ding X, Tang J, Cao Y, Hu P, Zhou F, Shan X, Cai X, Chen Q, Ling N, Zhang B, Bi Y, Chen K, Ren H, Huang A, He TC, Tang N (2011) Enhancement of canonical Wnt/beta-catenin signaling activity by HCV core protein promotes cell growth of hepatocellular carcinoma cells. PLoS One 6:e27496PubMedCrossRefGoogle Scholar
  14. Lu R, Liu X, Wu S, Xia Y, Zhang YG, Petrof EO, Claud EC, Sun J (2012) Consistent activation of the beta-catenin pathway by Salmonella type-three-secretion effector protein AvrA in chronically infected intestine. Am J Physiol Gastrointest Liver Physiol.Google Scholar
  15. Ma J, Wang R, Fang X, Sun Z (2012) b-catein/TCF-1 pathway in T cell development and differentiation. J. NeuroImmune Pharmacol. (this issue)Google Scholar
  16. Maguschak KA, Ressler KJ (2008) Beta-catenin is required for memory consolidation. Nat Neurosci 11:1319–1326PubMedCrossRefGoogle Scholar
  17. Maguschak KA, Ressler KJ (2012) A Role for WNT/beta-Catenin Signaling in the Neural Mechanisms of Behavior. J Neuroimmune Pharmacol (this issue)Google Scholar
  18. Mikels AJ, Nusse R (2006) Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 4:e115PubMedCrossRefGoogle Scholar
  19. Mulligan KA, Cheyette BN (2012) Wnt Signaling in Vertebrate Neural Development and Function. J Neuroimmune Pharmacol (this issue) Google Scholar
  20. Nusse R, Varmus HE (1982) Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31:99–109PubMedCrossRefGoogle Scholar
  21. Nusse R, Varmus H (2012) Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J 31:2670–2684PubMedCrossRefGoogle Scholar
  22. Nusslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287:795–801PubMedCrossRefGoogle Scholar
  23. Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC, Mundlos S, Shibuya H, Takada S, Minami Y (2003) The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8:645–654PubMedCrossRefGoogle Scholar
  24. Ozawa M, Baribault H, Kemler R (1989) The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J 8:1711–1717PubMedGoogle Scholar
  25. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000) An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407:535–538PubMedCrossRefGoogle Scholar
  26. Rampias T, Boutati E, Pectasides E, Sasaki C, Kountourakis P, Weinberger P, Psyrri A (2010) Activation of Wnt signaling pathway by human papillomavirus E6 and E7 oncogenes in HPV16-positive oropharyngeal squamous carcinoma cells. Mol Cancer Res 8:433–443PubMedCrossRefGoogle Scholar
  27. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P (1993) Association of the APC gene product with beta-catenin. Science 262:1731–1734PubMedCrossRefGoogle Scholar
  28. Shackelford J, Maier C, Pagano JS (2003) Epstein-Barr virus activates beta-catenin in type III latently infected B lymphocyte lines: association with deubiquitinating enzymes. Proc Natl Acad Sci U S A 100:15572–15576PubMedCrossRefGoogle Scholar
  29. Shi Y, Gelman BB, Lisinicchia JG, Tang SJ (2012a) Chronic-pain-associated astrocytic reaction in the spinal cord dorsal horn of human immunodeficiency virus-infected patients. J Neurosci 32:10833–10840PubMedCrossRefGoogle Scholar
  30. Shi Z, Qian X, Li L, Zhnag J, Zhu S, Zhu J, Chen L, Zhang K, Han L, Yu S, Pu P, Jiang T, Kang C (2012b) Nuclear translocation of b-catenin is essential for glioma cell survival. J NeuroImmune Pharmacol (this issue)Google Scholar
  31. Siegfried E, Chou TB, Perrimon N (1992) wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate. Cell 71:1167–1179PubMedCrossRefGoogle Scholar
  32. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X (2000) LDL-receptor-related proteins in Wnt signal transduction. Nature 407:530–535PubMedCrossRefGoogle Scholar
  33. Yang-Snyder J, Miller JR, Brown JD, Lai CJ, Moon RT (1996) A frizzled homolog functions in a vertebrate Wnt signaling pathway. Curr Biol 6:1302–1306PubMedCrossRefGoogle Scholar
  34. Yoshikawa S, McKinnon RD, Kokel M, Thomas JB (2003) Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature 422:583–588PubMedCrossRefGoogle Scholar
  35. Zhang K, Zhang J, Han L, Pu P, Kang C (2012) Wnt/beta-catenin signaling in gliomas. J NeuroImmune Pharmacol (this issue)Google Scholar

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© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Immunology and MicrobiologyRush University Medical CenterChicagoUSA

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