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Integrin β4 in Neural Cells

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Abstract

Integrin β4, one of the heterodimeric receptors, is expressed predominantly on epithelial cells. It is concentrated at the basement membrane zone, where it localizes to specialized adhesion structures called hemidesmosomes. In addition to its adhesive functions, novel insights have emerged regarding the specific roles of integrin β4 in their attachment to extracellular matrix and in their signal transduction pathways within the central nervous system (CNS) and peripheral nervous system in the past few years. It has been reported that integrin β4 is expressed in several kinds of neural cells including astrocyte, Schwann cells, neurons, and neural stem cells. In the mean while, it is expressed by some Schwann cells in the peripheral nervous system and mediated the Mycobacterium leprae invade the peripheral nervous system to reach the Schwann cells. This review highlights recent progress in the function and regulation of integrin β4 in neural cells.

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References

  • Abbruscato, T., & Davis, T. (1999). Protein expression of brain endothelial cell E-cadherin after hypoxia/aglycemia: Influence of astrocyte contact. Brain Research, 842, 277–286.

    Article  PubMed  CAS  Google Scholar 

  • Amici, S. A., Dunn, W. A., Jr., Murphy, A. J., Adams, N. C., Gale, N. W., Valenzuela, D. M., et al. (2006). Peripheral myelin protein 22 is in complex with alpha6beta4 integrin, and its absence alters the Schwann cell basal lamina. Journal of Neuroscience, 26, 1179–1189.

    Article  PubMed  CAS  Google Scholar 

  • Anton, E. S., Kreidberg, J. A., & Rakic, P. (1999). Distinct functions of α3 and α(v) integrin receptors in neuronal migration and laminar organization of the cerebral cortex. Neuron, 22, 277–289.

    Article  PubMed  CAS  Google Scholar 

  • Ballabh, P., Braun, A., & Nedergaard, M. (2004). The blood–brain barrier: An overview. Structure, regulation and clinical implications. Neurobiology of Disease, 16, 1–13.

    CAS  Google Scholar 

  • Belot, N., Rorive, S., Doyen, I., Lefranc, F., Bruyneel, E., Dedecker, R., et al. (2001). Molecular characterization of cell substratum attachments in human glial tumors relates to prognostic features. Glia, 36, 375–390.

    Article  PubMed  CAS  Google Scholar 

  • Berti, C., Nodari, A., Wrabetz, L., & Feltri, M. L. (2006). Role of integrins in peripheral nerves and hereditary neuropathies. Neuromolecular Medcine, 8, 191–204.

    Article  CAS  Google Scholar 

  • Bertotti, A., Comoglio, P. M., & Trusolino, L. (2005). β4 integrin is a transforming molecule that unleashes Met tyrosine kinase tumorigenesis. Cancer Research, 65, 10674–10679.

    Article  PubMed  CAS  Google Scholar 

  • Bertotti, A., Comoglio, P. M., & Trusolino, L. (2006). Beta4 integrin activates a Shp2-Src signaling pathway that sustains HGF-induced anchorage-independent growth. Journal of Cell Biology, 175, 993–1003.

    Article  PubMed  CAS  Google Scholar 

  • Clarke, A. S., Lotz, M. M., Chao, C. C., & Mercurio, A. M. (1995). Activation of the p21 pathway of growth arrest and apoptosis by the beta 4 integrin cytoplasmic domain. Journal of Biological Chemistry, 270, 22673–22676.

    Article  PubMed  CAS  Google Scholar 

  • Dowling, J., Yu, Q. C., & Fuchs, E. (1996). Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. Journal of Cell Biology, 134, 559–572.

    Article  PubMed  CAS  Google Scholar 

  • Einheber, S., Milner, T. A., Giancotti, F., & Salzer, J. L. (1993). Axonal regulation of Schwann cell integrin expression suggests a role for alpha 6 beta 4 in myelination. Journal of Cell Biology, 123, 1223–1236.

    Article  PubMed  CAS  Google Scholar 

  • Fasen, K., Elger, C. E., & Lie, A. A. (2003). Distribution of alpha and beta integrin subunits in the adult rat hippocampus after pilocarpine-induced neuronal loss, axonal reorganization and reactive gliosis. Acta Neuropathologica, 106, 319–322.

    Article  PubMed  CAS  Google Scholar 

  • Feltri, M. L., Scherer, S. S., Nemni, R., Kamholz, J., Vogelbacker, H., Scott, M. O., et al. (1994). Beta 4 integrin expression in myelinating Schwann cells is polarized, developmentally regulated and axonally dependent. Development, 120, 1287–1301.

    Google Scholar 

  • Flanagan, L. A., Rebaza, L. M., Derzic, S., Schwartz, P. H., & Monuki, E. S. (2006). Regulation of human neural precursor cells by laminin and integrins. Journal of Neuroscience Research, 83, 845–856.

    Article  PubMed  CAS  Google Scholar 

  • Frei, R., Dowling, J., Carenini, S., Fuchs, E., & Martini, R. (1999). Myelin formation by Schwann cells in the absence of beta4 integrin. Glia, 3, 269–274.

    Article  Google Scholar 

  • Gama Sosa, M. A., De Gasperi, R., Rocher, A. B., Perez, G. M., Simons, K., Cruz, D. E., et al. (2007). Interactions of primary neuroepithelial progenitor and brain endothelial cells: Distinct effect on neural progenitor maintenance and differentiation by soluble factors and direct contact. Cell Research, 17, 619–626.

    Article  PubMed  CAS  Google Scholar 

  • Georges-Labouesse, E., Mark, M., Messaddeq, N., & Gansmüller, A. (1998). Essential role of alpha 6 integrins in cortical and retinal lamination. Current Biology, 8, 983–986.

    Article  PubMed  CAS  Google Scholar 

  • Graus-Porta, D., Blaess, S., Senften, M., Littlewood-Evans, A., Damsky, C., Huang, Z., et al. (2001). Beta1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex. Neuron, 31, 367–379.

    Article  PubMed  CAS  Google Scholar 

  • Guo, W., Pylayeva, Y., Pepe, A., Yoshioka, T., Muller, W. J., Inghirami, G., et al. (2006). Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell, 126, 489–502.

    Article  PubMed  CAS  Google Scholar 

  • Hall, P. E., Lathia, J. D., Miller, N. G., Caldwell, M. A., & Ffrench-Constant, C. (2006). Integrins are markers of human neural stem cells. Stem Cells, 24, 2078–2084.

    Article  PubMed  CAS  Google Scholar 

  • Hogervorst, F., Kuikman, I., Borne, A., & Sonnenberg, A. (1990). Cloning and sequence analysis of beta–4 cDNA: An integrin subunit that contains a unique 118 kd cytoplasmic domain. EMBO Journal, 9, 756–770.

    Google Scholar 

  • Hsiao, L. L., Peltonen, J., Jaakkola, S., Gralnick, H., & Uitto, J. (1991). Plasticity of integrin expression by nerve-derived connective tissue cells. Journal of Clinical Investigation, 87, 811–820.

    Article  PubMed  CAS  Google Scholar 

  • Hynes, R. O., Bader, B. L., & Hodivala-Dilke, K. (1999). Integrins in vascular development. Brazilian Journal of Medical and Biological Research, 32, 501–510.

    Article  PubMed  CAS  Google Scholar 

  • Hynes, R. O., Lively, J. C., McCarty, J. H., Taverna, D., Francis, S. E., Hodivala-Dilke, K., et al. (2002). The diverse roles of integrins and their ligands in angiogenesis. Cold Spring Harbor Symposia on Quantitative Biology, 67, 143–153.

    Article  PubMed  CAS  Google Scholar 

  • Jaakkola, S., Savunen, O., Halme, T., Uitto, J., & Peltonen, J. (1993). Basement membranes during development of human nerve: Schwann cells and perineurial cells display marked changes in their expression profiles for laminin subunits and β1 and β4 integrins. Journal of Neurocytology, 22, 215–230.

    Article  PubMed  CAS  Google Scholar 

  • Jacques, T. S., Relvas, J. B., Nishimura, S., Pytela, R., Edwards, G. M., Streuli, C. H., et al. (1998). Neural precursor cell chain migration and division are regulated through different beta1 integrins. Development, 125, 3167–3177.

  • Job, C. K. (1989). Nerve damage in leprosy. International Journal of Leprosy, 57, 532–539.

    CAS  Google Scholar 

  • Kerber, G., Streif, R., Schwaiger, F. W., Kreutzberg, G. W., & Hager, G. (2003). Neuregulin–1 isoforms are differentially expressed in the intact and regenerating adult rat nervous system. Journal of Molecular Neuroscience, 21, 149–165.

    Article  PubMed  CAS  Google Scholar 

  • Kloss, C. U., Werner, A., Klein, M. A., Shen, J., Menuz, K., Probst, J. C., et al. (1999). Integrin family of cell adhesion molecules in the injured brain: Regulation and cellular localization in the normal and regenerating mouse facial motor nucleus. Journal of Comparative Neurology, 411, 162–178.

    Article  PubMed  CAS  Google Scholar 

  • Lauffenburger, D. A., & Horwitz, A. F. (1996). Cell migration: A physically integrated molecular process. Cell, 84, 359–369.

    Article  PubMed  CAS  Google Scholar 

  • Lefcort, F., Venstrom, K., McDonald, J. A., & Reichardt, L. F. (1992). Regulation of expression of fibronectin and its receptor, α5β1, during developing and regeneration of peripheral nerve. Development, 116, 767–782.

    PubMed  CAS  Google Scholar 

  • Litjens, S. H., de Pereda Sonnenberg A., J. M., & Sonnenberg, A. (2006). Current insights into the formation and breakdown of hemidesmosomes. Trends in Cell Biology, 16, 376–383.

    Article  PubMed  CAS  Google Scholar 

  • Lv X., Su L., Yin D., Sun C., Zhao J., Zhang S., & Miao J. (2007). Knockdown of integrin beta4 in primary cultured mouse neurons blocks survival and induces apoptosis by elevating NADPH oxidase activity and reactive oxygen species level. The International Journal of Biochemistry & Cell Biology. [Epub ahead of print].

  • Lv, X., Wang, N., Su, L., Zhang, S., & Miao, J. (2006). Inhibition of PC-PLC blocked the survival of mouse neural cells by up-regulating the expression of integrin beta4 and Rb. Developmental Neuroscience, 28, 499–504.

    Article  PubMed  CAS  Google Scholar 

  • Mariotti, A., Kedeshian, P. A., Dans, M., Curatola, A. M., Gagnoux-Palacios, L., & Giancotti, F. G. (2001). EGF-R signaling through Fyn kinase disrupts the function of integrin α6β4 at hemidesmosomes: Role in epithelial cell migration and carcinoma invasion. Journal of Cell Biology, 155, 447–458.

    Article  PubMed  CAS  Google Scholar 

  • Masaki, T., Matsumura, K., Saito, F., Sunada, Y., Shimizu, T., Yorifuji, H., et al. (2000). Expression of dystroglycan and laminin-2 in peripheral nerve under axonal degeneration and regeneration. Acta Neuropathologica, 99, 289–295.

    Article  PubMed  CAS  Google Scholar 

  • McCarty, J. H., Lacy-Hulbert, A., Charest, A., Bronson, R. T., Crowley, D., Housman, D., et al. (2005). Selective ablation of alphav integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death. Development, 132, 165–176.

    Article  PubMed  CAS  Google Scholar 

  • Mercurio, A. M., & Rabinovitz, I. (2001). Towards a mechanistic understanding of tumor invasion-lessons from the alpha 6 beta 4 integrin. Seminars in Cancer Biology, 11, 129–141.

    Article  PubMed  CAS  Google Scholar 

  • Mercurio, A. M., Rabinovitz, I., & Shaw, L. M. (2001). The alpha 6 beta 4 integrin and epithelial cell migration. Current Opinion in Cell Biology, 13, 541–545.

    Article  PubMed  CAS  Google Scholar 

  • Milner, R., & Campbell, I. L. (2006). Increased expression of the beta4 and alpha5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-alpha in the central nervous system. Molecular and Cellular Neurosciences, 33, 429–440.

    Article  PubMed  CAS  Google Scholar 

  • Niessen, C. M., Cremona, O., Daams, H., Ferraresi, S., Sonnenberg, A., & Marchisio, P. C. (1994). Expression of the integrin alpha 6 beta 4 in peripheral nerves: Localization in Schwann and perineural cells and different variants of the beta 4 subunit. Journal of Cell Science, 107, 543–552.

    PubMed  CAS  Google Scholar 

  • Noordeen, S. K., Lopez, B. L., & Sundaresan, T. K. (1992). Estimated number of leprosy cases in the world. Bulletin of the World Health Organization, 70, 7–10.

    PubMed  CAS  Google Scholar 

  • Oldak, M., Smola-Hess, S., & Maksym, R. (2006). Integrin beta4, keratinocytes and papillomavirus infection. International Journal of Molecular Medicine, 17, 195–202.

    PubMed  CAS  Google Scholar 

  • Pardridge, W. M. (2003). Blood–brain barrier drug targeting: The future of brain drug development. Molecular Medicine, 3, 90–105.

    CAS  Google Scholar 

  • Paulus, W., Baur, I., Schuppan, D., & Roggendorf, W. (1993). Characterisation of integrin receptors in normal and neoplastic brain. American Journal of Pathology, 143, 154–163.

    PubMed  CAS  Google Scholar 

  • Previtali, S., Archelos, J., & Hartung, H. P. (1997). Modulation of the expression of integrins on glial cells during experimental autoimmune encephalomyelitis. American Journal of Pathology, 151, 1425–1435.

    PubMed  CAS  Google Scholar 

  • Previtali, S., Feltri, M., Archelos, J., Quattrini, A., Wrabetz, L., & Hartung, H. P. (2001). Role of integrins in the peripheral nervous system. Progress in Neurobiology, 64, 35–49.

    Article  PubMed  CAS  Google Scholar 

  • Previtali, S. C., Nodari, A., Taveggia, C., Pardini, C., Dina, G., Villa, A., et al. (2003). Expression of laminin receptors in schwann cell differentiation: Evidence for distinct roles. Journal of Neuroscience, 23, 5520–5530.

    PubMed  CAS  Google Scholar 

  • Previtali, S. C., Quattrini, A., Nemni, R., Truci, G., Ducati, A., Wrabetz, L., et al. (1996a). α6β4 and α6β1 integrins in astrocytomas, and other CNS tumours. Journal of Neuropathology and Experimental Neurology, 55, 456–465.

    Article  PubMed  CAS  Google Scholar 

  • Previtali, S. C., Quattrini, A., Nemni, R., Truci, G., Wrabetz, L., & Canal, N. (1996b). α6β4 integrin expression in ENU-induced gliomas. Journal of Neuro-Oncology, 30, 148.

    Google Scholar 

  • Quattrini, A., Previtali, S., Feltri, M. L., Canal, N., Nemni, R., & Wrabetz, L. (1996). β4 integrin and other Schwann cell markers in axonal neuropathy. Glia, 17, 294–306.

    Article  PubMed  CAS  Google Scholar 

  • Rambukkana, A., Salzer, J. L., Yurchenco, P. D., & Tuomanen, E. I. (1997). Neural targeting of Mycobacterium leprae mediated by the G domain of the laminin-alpha2 chain. Cell, 88, 811–821.

    Article  PubMed  CAS  Google Scholar 

  • Risau, W., Esser, S., & Engelhardt, B. (1998). Differentiation of blood–brain barrier endothelial cells. Pathologie Biologie, 46, 171–175.

    PubMed  CAS  Google Scholar 

  • Schmid, R. S., & Anton, E. S. (2003). Role of integrins in the development of the cerebral cortex. Cerebral Cortex, 13, 219–224.

    Article  PubMed  Google Scholar 

  • Schmid, R. S., Shelton, S., Stanco, A., Yokota, Y., Kreidberg, J. A., & Anton, E. S. (2004). Alpha3beta1 integrin modulates neuronal migration and placement during early stages of cerebral cortical development. Development, 131, 6023–6031.

    Article  PubMed  CAS  Google Scholar 

  • Shaw, C. E., Milner, R., Compston, A. S., & Ffrench-Constant, C. (1996). Analysis of integrin expression on oligodendrocytes during axo-glial interaction by using rat-mouse xenocultures. Journal of Neuroscience, 16, 1163–1172.

    PubMed  CAS  Google Scholar 

  • Shen, Q., Goderie, S. K., Jin, L., Karanth, N., Sun, Y., Abramova, N., et al. (2004). Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science, 304, 1338–1340.

    Article  PubMed  CAS  Google Scholar 

  • Sherman, D. L., & Brophy, P. J. (2005). Mechanisms of axon ensheathment and myelin growth. Nature Reviews. Neuroscience, 6, 683–690.

    Article  PubMed  CAS  Google Scholar 

  • Sonnenberg, A., Linders, C. J., Daams, J. H., & Kennel, S. J. (1990). The α6β1 (VLA-6) and α6β4 protein complexes: Tissue distribution and biochemical properties. Journal of Cell Science, 96, 207–217.

    PubMed  CAS  Google Scholar 

  • Stromblad, S., & Cheresh, D. A. (1996). Integrins, angiogenesis and vascular cell survival. Chemical Biology, 3, 881–885.

    Article  CAS  Google Scholar 

  • Su, L., Zhao, B., Lv, X., Wang, N., Zhao, J., Zhang, S., et al. (2007a). Safrole oxide induces neuronal apoptosis through inhibition of integrin beta4/SOD activity and elevation of ROS/NADPH oxidase activity. Life Sciences, 80, 999–1006.

    Article  PubMed  CAS  Google Scholar 

  • Su, L., Zhao, B., Lv, X., Zhao, J., Zhang, S., & Miao, J. (2007b). Safrole oxide is a useful tool for investigating the effect of apoptosis in vascular endothelial cells on neural stem cell survival and differentiation in vitro. Bioorganic & Medicinal Chemistry Letters, 17, 3167–3171.

    Article  CAS  Google Scholar 

  • Suzuki, S., & Naitoh, Y. (1990). Amino acid sequence of a novel integrin β4 subunit and primary expression of the mRNA in epithelial cells. EMBO Journal, 9, 757–763.

    PubMed  CAS  Google Scholar 

  • Tamura, R. N., Rozzo, C., Starr, L., Chambers, J., Reichardt, L. F., Cooper, H. M., et al. (1990). Epithelial integrin alpha 6 beta 4: Complete primary structure of alpha 6 and variant forms of beta 4. Journal of Cell Biology, 111, 1593–1604.

    Article  PubMed  CAS  Google Scholar 

  • Tarone, G., Hirsch, E., Brancaccio, M., De Acetis, M., Barberis, L., Balzac, F., et al. (2000). Integrin function and regulation in development. International Journal of Developmental Biology, 44, 725–731.

    PubMed  CAS  Google Scholar 

  • Toyota, B., Carbonetto, S., & David, S. (1990). A dual laminin/collagen receptor acts in peripheral nerve regeneration. Proceedings of the National Academy of Science, 87, 1319–1322.

    Article  CAS  Google Scholar 

  • Trusolino, L., Bertotti, A., & Comoglio, P. M. (2001). A signaling adapter function for α6β4 integrin in the control of HGF-dependent invasive growth. Cell, 107, 643–654.

    Article  PubMed  CAS  Google Scholar 

  • Wagner, S., Tagaya, M., Koziol, J., Quaranta, V., & del Zoppo, G. J. (1997). Rapid disruption of an astrocyte interaction with the extracellular matrix mediated by integrin α6β4 during focal cerebral ischemia/reperfusion. Stroke, 28, 858–865.

    PubMed  CAS  Google Scholar 

  • Whitley, M., Treloar, H., De Arcangelis, A., Georges Labouesse, E., & Greer, C. A. (2005). The alpha6 integrin subunit in the developing mouse olfactory bulb. Journal of Neurocytology, 34, 81–96.

    Article  PubMed  CAS  Google Scholar 

  • Xie, Z., Zhong, Y., Yang, J., Zhang, Q., Wang, S., Wang, W., et al. (2003). Integrin alpha6 beta4 and experimental allergic neuritis. Beijing Da Xue Xue Bao, 35, 605–608.

    PubMed  CAS  Google Scholar 

  • Zhang, Z., & Galileo, D. S. (1998). Retroviral transfer of antisense integrin alpha6 or alpha8 sequences results in laminar redistribution or clonal cell death in developing brain. The Journal of Neuroscience, 18, 6928–6938.

    PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported by National Natural Science Foundation of China. (No. 30470404), the National 973 Research Project (No.2006CB503803).

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Correspondence to JunYing Miao.

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Su, L., Lv, X. & Miao, J. Integrin β4 in Neural Cells. Neuromol Med 10, 316–321 (2008). https://doi.org/10.1007/s12017-008-8042-1

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