NGF/P75 in Cell Cycle and Tetraploidy

  • Noelia López-Sánchez
  • María Carmen Ovejero-Benito
  • Claudia Rodríguez-Ruiz
  • José María Frade
Reference work entry


Neurotoxicity, neurodegeneration, and other disorders affecting neuron survival are often related to cell cycle reentry in neurons. Traditionally, cell cycle reentry of these postmitotic cells has been thought to be associated with apoptosis. Nevertheless, cell cycle reentry and DNA synthesis in neurons could also lead to tetraploidy which may explain long-lasting neurodegenerative processes. During development, a subpopulation of newborn neurons reactivates the cell cycle and becomes tetraploid in response to p75NTR activation. These neurons enlarge their cell bodies and increase their dendritic trees, thus generating specific neuronal populations that innervate particular areas. Pathological states in the nervous system could also lead to p75NTR-dependent neuronal tetraploidy. De novo tetraploid neurons might become structurally and functionally altered, thus leading to neurodegeneration at late stages of the disease. This chapter describes what is currently known about the interplay between p75NTR and the cell cycle, stressing the role played by different p75NTR interactors, including the MAGE and Bex1/NADE adaptor proteins and the transcription factors SC1, NRIF, and Sall2, in cell cycle regulation. The chapter also discusses on the effects of p75NTR, as a cell cycle regulator, in neural stem cell proliferation, neurogenesis, and neuronal tetraploidization, as well as on the connection of p75NTR in pathology, including its putative effects in neurodegeneration.


Amyotrophic Lateral Sclerosis Adult Neurogenesis Regulate Cell Cycle Progression Adult Nervous System Vertebrate Nervous System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

List of Abbreviations



Brain-derived neurotrophic factor


Brain-expressed X-linked 1




Cyclin-dependent kinase


Chicken MAGE


Central nervous system


Dlx/Msx-interacting MAGE/Necdin family protein


E2 promoter-binding factor-1


Enhanced green fluorescent protein


Extracellular signal-regulated kinase


c-Jun N-terminal kinase


Melanoma antigen


Mitogen-activated protein kinase


p75NTR-associated cell death executor


Nerve growth factor


Neurotrophin receptor-interacting MAGE homolog


Neurotrophin receptor-interacting factor




p75NTR intracellular domain


p75 neurotrophin receptor


Proliferating cell nuclear marker


Peripheral nervous system


Positive regulatory/suppressor of variegation, enhancer of zeste, trithorax




Retinal ganglion cells


Sal-like protein 2


Schwann cell factor 1


Subgranular zone


Subventricular zone


Tumor necrosis factor


Tropomyosin-related kinase


  1. Ambrosino, C., & Nebreda, A. R. (2001). Cell cycle regulation by p38 MAP kinases. Biology of the Cell, 93, 47–51.PubMedGoogle Scholar
  2. Anatskaya, O. V., & Vinogradov, A. E. (2007). Genome multiplication as adaptation to tissue survival: evidence from gene expression in mammalian heart and liver. Genomics, 89, 70–80.PubMedGoogle Scholar
  3. Arendt, T., Brückner, M. K., Mosch, B., & Lösche, A. (2010). Selective cell death of hyperploid neurons in Alzheimer’s disease. The American Journal of Pathology, 177, 15–20.PubMedCentralPubMedGoogle Scholar
  4. Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., & Lindvall, O. (2002). Neuronal replacement from endogenous precursors in the adult brain after stroke. Nature Medicine, 8, 963–970.PubMedGoogle Scholar
  5. Bannerman, P. G., & Pleasure, D. (1993). Protein growth factor requirements of rat neural crest cells. Journal of Neuroscience Research, 36, 46–57.PubMedGoogle Scholar
  6. Barde, Y. A., Edgar, D., & Thoenen, H. (1982). Purification of a new neurotrophic factor from mammalian brain. The EMBO Journal, 1, 549–553.PubMedCentralPubMedGoogle Scholar
  7. Barker, P. A., & Salehi, A. (2002). The MAGE proteins: emerging roles in cell cycle progression, apoptosis, and neurogenetic disease. Journal of Neuroscience Research, 67, 705–712.PubMedGoogle Scholar
  8. Becker, M., Lavie, V., & Solomon, B. (2007). Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 104, 1691–1696.PubMedCentralPubMedGoogle Scholar
  9. Benzel, I., Barde, Y. A., & Casademunt, E. (2001). Strain-specific complementation between NRIF1 and NRIF2, two zinc finger proteins sharing structural and biochemical properties. Gene, 281, 19–30.PubMedGoogle Scholar
  10. Berkemeier, L. R., Winslow, J. W., Kaplan, D. R., Nikolics, K., Goeddel, D. V., & Rosenthal, A. (1991). Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron, 7, 857–866.PubMedGoogle Scholar
  11. Bernabeu, R. O., & Longo, F. M. (2010). The p75 neurotrophin receptor is expressed by adult mouse dentate progenitor cells and regulates neuronal and non-neuronal cell genesis. BMC Neuroscience, 11, 136.PubMedCentralPubMedGoogle Scholar
  12. Burns, K. A., Ayoub, A. E., Breunig, J. J., Adhami, F., Weng, W. L., Colbert, M. C., Rakic, P., & Kuan, C. Y. (2007). Nestin-CreER mice reveal DNA synthesis by nonapoptotic neurons following cerebral ischemia hypoxia. Cerebral Cortex, 17, 2585–2592.PubMedGoogle Scholar
  13. Byrnes, K. R., Stoica, B. A., Fricke, S., Di Giovanni, S., & Faden, A. I. (2007). Cell cycle activation contributes to post-mitotic cell death and secondary damage after spinal cord injury. Brain, 130, 2977–2992.PubMedGoogle Scholar
  14. Calzà, L., Giardino, L., Pozza, M., Bettelli, C., Micera, A., & Aloe, L. (1998). Proliferation and phenotype regulation in the subventricular zone during experimental allergic encephalomyelitis: in vivo evidence of a role for nerve growth factor. Proceedings of the National Academy of Sciences of the United States of America, 95, 3209–3214.PubMedCentralPubMedGoogle Scholar
  15. Casaccia-Bonnefil, P., Carter, B. D., Dobrowsky, R. T., & Chao, M. V. (1996). Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature, 383, 716–719.PubMedGoogle Scholar
  16. Casademunt, E., Carter, B. D., Benzel, I., Frade, J. M., Dechant, G., & Barde, Y. A. (1999). The zinc finger protein NRIF interacts with the neurotrophin receptor p75NTR and participates in programmed cell death. The EMBO Journal, 18, 6050–6061.PubMedCentralPubMedGoogle Scholar
  17. Catts, V. S., Al-Menhali, N., Burne, T. H., Colditz, M. J., & Coulson, E. J. (2008). The p75 neurotrophin receptor regulates hippocampal neurogenesis and related behaviours. The European Journal of Neuroscience, 28, 883–892.PubMedGoogle Scholar
  18. Chao, M. V., Bothwell, M. A., Ross, A. H., Koprowski, H., Lanahan, A. A., Buck, C. R., & Sehgal, A. (1986). Gene transfer and molecular cloning of the human NGF receptor. Science, 232, 518–521.PubMedGoogle Scholar
  19. Chen, L. W., Yung, K. K., Chan, Y. S., Shum, D. K., & Bolam, J. P. (2008). The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson’s disease. CNS & Neurological Disorders Drug Targets, 7, 512–523.Google Scholar
  20. Chittka, A., & Chao, M. V. (1999). Identification of a zinc finger protein whose subcellular distribution is regulated by serum and nerve growth factor. Proceedings of the National Academy of Sciences of the United States of America, 96, 10705–10710.PubMedCentralPubMedGoogle Scholar
  21. Chittka, A., Arevalo, J. C., Rodriguez-Guzman, M., Pérez, P., Chao, M. V., & Sendtner, M. (2004). The p75NTR-interacting protein SC1 inhibits cell cycle progression by transcriptional repression of cyclin E. The Journal of Cell Biology, 164, 985–996.PubMedCentralPubMedGoogle Scholar
  22. Coggeshall, R. E., Yaksta, B. A., & Swartz, F. J. (1970). A cytophotometric analysis of the DNA in the nucleus of the giant cell, R-2, in Aplysia. Chromosoma, 32, 205–212.PubMedGoogle Scholar
  23. Cohen, S., Levi-Montalcini, R., & Hamburger, V. (1954). A nerve growth-stimulating factor isolated from sarcom AS 37 and 180. Proceedings of the National Academy of Sciences of the United States of America, 40, 1014–1018.PubMedCentralPubMedGoogle Scholar
  24. Colditz, M. J., Catts, V. S., Al-menhali, N., Osborne, G. W., Bartlett, P. F., & Coulson, E. J. (2010). p75 neurotrophin receptor regulates basal and fluoxetine-stimulated hippocampal neurogenesis. Experimental Brain Research, 200, 161–167.PubMedGoogle Scholar
  25. Costantini, C. F., Rossi, E., Formaggio, R., Bernardoni, D., Cecconi, V., & Della-Bianca, V. (2005). Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in beta-amyloid peptide-dependent cell death. Journal of Molecular Neuroscience, 25, 141–156.PubMedGoogle Scholar
  26. Curtis, M. A., Penney, E. B., Pearson, A. G., van Roon-Mom, W. M., Butterworth, N. J., Dragunow, M., Connor, B., & Faull, R. L. (2003). Increased cell proliferation and neurogenesis in the adult human Huntington’s disease brain. Proceedings of the National Academy of Sciences of the United States of America, 100, 9023–9027.PubMedCentralPubMedGoogle Scholar
  27. Dechant, G., & Barde, Y. A. (2002). The neurotrophin receptor p75NTR: novel functions and implications for diseases of the nervous system. Nature Neuroscience, 5, 1131–1136.PubMedGoogle Scholar
  28. Di Giovanni, S., Movsesyan, V., Ahmed, F., Cernak, I., Schinelli, S., Stoica, B., & Faden, A. I. (2005). Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proceedings of the National Academy of Sciences of the United States of America, 102, 8333–8888.PubMedCentralPubMedGoogle Scholar
  29. Edgar, B. A., & Orr-Weaver, T. L. (2001). Endoreplication cell cycles: more for less. Cell, 105, 297–306.PubMedGoogle Scholar
  30. Fahnestock, M., Michalski, B., Xu, B., & Coughlin, M. D. (2001). The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer’s disease. Molecular and Cellular Neurosciences, 18, 210–220.PubMedGoogle Scholar
  31. Fallon, J., Reid, S., Kinyamu, R., Opole, I., Opole, R., Baratta, J., Korc, M., Endo, T. L., Duong, A., Nguyen, G., Karkehabadhi, M., Twardzik, D., Patel, S., & Loughlin, S. (2000). In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain. Proceedings of the National Academy of Sciences of the United States of America, 97, 14686–14691.PubMedCentralPubMedGoogle Scholar
  32. Fernandez-Fernandez, M. R., Ferrer, I., & Lucas, J. J. (2011). Impaired ATF6α processing, decreased Rheb and neuronal cell cycle re-entry in Huntington’s disease. Neurobiology of Disease, 41, 23–32.PubMedGoogle Scholar
  33. Ferraiuolo, L., Heath, P. R., Holden, H., Kasher, P., Kirby, J., & Shaw, P. J. (2007). Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS. The Journal of Neuroscience, 27, 9201–9219.PubMedGoogle Scholar
  34. Foltz, G., Ryu, G. Y., Yoon, J. G., Nelson, T., Fahey, J., Frakes, A., Lee, H., Field, L., Zander, K., Sibenaller, Z., Ryken, T. C., Vibhakar, R., Hood, L., & Madan, A. (2006). Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma. Cancer Research, 66, 6665–6674.PubMedGoogle Scholar
  35. Frade, J. M. (2000). Unscheduled re-entry into the cell cycle induced by NGF precedes cell death in nascent retinal neurones. Journal of Cell Science, 113, 1139–1148.PubMedGoogle Scholar
  36. Frade, J. M. (2005). Nuclear translocation of the p75 neurotrophin receptor cytoplasmic domain in response to neurotrophin binding. The Journal of Neuroscience, 25, 1407–1411.PubMedGoogle Scholar
  37. Frade, J. M., & Barde, Y. A. (1999). Genetic evidence for cell death mediated by nerve growth factor and the neurotrophin receptor p75 in the developing mouse retina and spinal cord. Development, 126, 683–690.PubMedGoogle Scholar
  38. Frade, J. M., & López-Sánchez, N. (2010). A novel hypothesis for Alzheimer disease based on neuronal tetraploidy induced by p75NTR. Cell Cycle, 9, 1934–1941.PubMedGoogle Scholar
  39. Frade, J. M., Bovolenta, P., Martínez-Morales, J. R., Arribas, A., Barbas, J. A., & Rodríguez-Tébar, A. (1997). Control of early cell death by BDNF in the chick retina. Development, 124, 3313–3320.PubMedGoogle Scholar
  40. Fritz, M. D., Mirnics, Z. K., Nylanderm, K. D., & Schor, N. F. (2006). p75NTR enhances PC12 cell tumor growth by a non-receptor mechanism involving downregulation of cyclin D2. Experimental Cell Research, 312, 3287–3297.PubMedGoogle Scholar
  41. Gentry, J. J., Rutkoski, N. J., Burke, T. L., & Carter, B. D. (2004). A functional interaction between the p75 neurotrophin receptor interacting factors, TRAF6 and NRIF. The Journal of Biological Chemistry, 279, 16646–16656.PubMedGoogle Scholar
  42. Giuliani, A., D’Intino, G., Paradisi, M., Giardino, L., & Calzà, L. (2004). p75NTR-immunoreactivity in the subventricular zone of adult male rats: expression by cycling cells. Journal of Molecular Histology, 35, 749–758.PubMedGoogle Scholar
  43. Greenberg, M. E., Xu, B., Lu, B., & Hempstead, B. L. (2009). New insights in the biology of BDNF synthesis and release: implications in CNS function. The Journal of Neuroscience, 29, 12764–12767.PubMedCentralPubMedGoogle Scholar
  44. Hallböök, F., Ibáñez, C. F., & Persson, H. (1991). Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Neuron, 6, 845–858.PubMedGoogle Scholar
  45. Hapner, S. J., Boeshore, K. L., Large, T. H., & Lefcort, F. (1998). Neural differentiation promoted by truncated trkC receptors in collaboration with p75NTR. Developmental Biology, 201, 90–100.PubMedGoogle Scholar
  46. Höglinger, G. U., Breunig, J. J., Depboylu, C., Rouaux, C., Michel, P. P., Alvarez-Fischer, D., Boutillier, A. L., Degregori, J., Oertel, W. H., Rakic, P., Hirsch, E. C., & Hunot, S. (2007). The pRb/E2F cell-cycle pathway mediates cell death in Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America, 104, 3585–3590.PubMedCentralPubMedGoogle Scholar
  47. Hohn, A., Leibrock, J., Bailey, K., & Barde, Y. A. (1990). Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature, 344, 339–341.PubMedGoogle Scholar
  48. Hosomi, S., Yamashita, T., Aoki, M., & Tohyama, M. (2003). The p75 receptor is required for BDNF-induced differentiation of neural precursor cells. Biochemical and Biophysical Research Communications, 301, 1011–1015.PubMedGoogle Scholar
  49. Hu, X. Y., Zhang, H. Y., Qin, S., Xu, H., Swaab, D. F., & Zhou, J. N. (2002). Increased p75NTR expression in hippocampal neurons containing hyperphosphorylated tau in Alzheimer patients. Experimental Neurology, 178, 104–111.PubMedGoogle Scholar
  50. Huang, E. J., & Reichardt, L. F. (2001). Neurotrophins: roles in neuronal development and function. Annual Review of Neuroscience, 24, 677–736.PubMedCentralPubMedGoogle Scholar
  51. Jiang, Y., Chen, G., Zhang, Y., Lu, L., Liu, S., & Cao, X. (2007). Nerve growth factor promotes TLR4 signaling-induced maturation of human dendritic cells in vitro through inducible p75NTR. Journal of Immunology, 179, 6297–6304.Google Scholar
  52. Jin, H., Pan, Y., Zhao, L., Zhai, H., Li, X., Sun, L., He, L., Chen, Y., Hong, L., Du, Y., & Fan, D. (2007). p75 neurotrophin receptor suppresses the proliferation of human gastric cancer cells. Neoplasia, 9, 471–478.PubMedCentralPubMedGoogle Scholar
  53. Johnson, D., Lanahan, A., Buck, C. R., Sehgal, A., Morgan, C., Mercer, E., Bothwell, M., & Chao, M. (1986). Expression and structure of the human NGF receptor. Cell, 47, 545–554.PubMedGoogle Scholar
  54. Jones, K. R., & Reichardt, L. F. (1990). Molecular cloning of a human gene that is a member of the nerve growth factor family. Proceedings of the National Academy of Sciences of the United States of America, 87, 8060–8064.PubMedCentralPubMedGoogle Scholar
  55. Kanning, K. C., Hudson, M., Amieux, P. S., Wiley, J. C., Bothwell, M., & Schecterson, L. C. (2003). Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability. The Journal of Neuroscience, 23, 5425–5436.PubMedGoogle Scholar
  56. Kaplan, D. R., Hempstead, B. L., Martin-Zanca, D., Chao, M. V., & Parada, L. F. (1991). The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science, 252, 554–558.PubMedGoogle Scholar
  57. Kawaguchi, J., Kano, K., & Naito, K. (2009). Expression profiling of tetraploid mouse embryos in the developmental stages using a cDNA microarray analysis. The Journal of Reproduction and Development, 55, 670–675.PubMedGoogle Scholar
  58. Kenchappa, R. S., Zampieri, N., Chao, M. V., Barker, P. A., Teng, H. K., Hempstead, B. L., & Carter, B. D. (2006). Ligand-dependent cleavage of the p75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons. Neuron, 50, 219–232.PubMedGoogle Scholar
  59. Kenchappa, R. S., Tep, C., Korade, Z., Urra, S., Bronfman, F. C., Yoon, S. O., & Carter, B. D. (2010). p75 neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-alpha-converting enzyme/ADAM17. The Journal of Biological Chemistry, 285, 20358–20368.PubMedCentralPubMedGoogle Scholar
  60. Khwaja, F., & Djakiew, D. (2003). Inhibition of cell-cycle effectors of proliferation in bladder tumor epithelial cells by the p75NTR tumor suppressor. Molecular Carcinogenesis, 36, 153–160.PubMedGoogle Scholar
  61. Khwaja, F., Tabassum, A., Allen, J., & Djakiew, D. (2006). The p75NTR tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells. Biochemical and Biophysical Research Communications, 341, 1184–1192.PubMedGoogle Scholar
  62. Klein, R., Jing, S. Q., Nanduri, V., O’Rourke, E., & Barbacid, M. (1991a). The trk proto-oncogene encodes a receptor for nerve growth factor. Cell, 65, 189–197.PubMedGoogle Scholar
  63. Klein, R., Nanduri, V., Jing, S. A., Lamballe, F., Tapley, P., Bryant, S., Cordon-Cardo, C., Jones, K. R., Reichardt, L. F., & Barbacid, M. (1991b). The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell, 66, 395–403.PubMedCentralPubMedGoogle Scholar
  64. Klein, R., Lamballe, F., Bryant, S., & Barbacid, M. (1992). The trkB tyrosine protein kinase is a receptor for neurotrophin-4. Neuron, 8, 947–956.PubMedGoogle Scholar
  65. Krygier, S., & Djakiew, D. (2001). The neurotrophin receptor p75NTR is a tumor suppressor in human prostate cancer. Anticancer Research, 21, 3749–3755.PubMedGoogle Scholar
  66. Kuan, C. Y., Schloemer, A. J., Lu, A., Burns, K. A., Weng, W. L., Williams, M. T., Strauss, K. I., Vorhees, C. V., Flavell, R. A., Davis, R. J., Sharp, F. R., & Rakic, P. (2004). Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. The Journal of Neuroscience, 24, 10763–10772.PubMedCentralPubMedGoogle Scholar
  67. Kuwako, K., Taniura, H., & Yoshikawa, K. (2004). Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor. The Journal of Biological Chemistry, 279, 1703–1712.PubMedGoogle Scholar
  68. Lamballe, F., Klein, R., & Barbacid, M. (1991). trkC a new member of the trk family of tyrosine protein kinases is a receptor for neurotrophin-3. Cell, 66, 967–979.PubMedGoogle Scholar
  69. Lee, R., Kermani, P., Teng, K. K., & Hempstead, B. L. (2001). Regulation of cell survival by secreted proneurotrophins. Science, 294, 1945–1948.PubMedGoogle Scholar
  70. Levi-Montalcini, R., & Hamburger, V. (1951). Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. The Journal of Experimental Zoology, 116, 321–361.PubMedGoogle Scholar
  71. Li, H. Y., Say, E. H., & Zhou, X. F. (2007). Isolation and characterization of neural crest progenitors from adult dorsal root ganglia. Stem Cells, 25, 2053–2065.PubMedGoogle Scholar
  72. López-Sánchez, N., & Frade, J. M. (2002). Control of the cell cycle by neurotrophins: lessons from the p75 neurotrophin receptor. Histology and Histopathology, 17, 1227–1237.PubMedGoogle Scholar
  73. López-Sánchez, N., González-Fernández, Z., Niinobe, M., Yoshikawa, K., & Frade, J. M. (2007). Single mage gene in the chicken genome encodes CMage, a protein with functional similarities to mammalian type II Mage proteins. Physiological Genomics, 30, 156–171.PubMedGoogle Scholar
  74. López-Sánchez, N., Ovejero-Benito, M. C., Borreguero, L., & Frade, J. M. (2011). Control of neuronal ploidy during vertebrate development. Results and Problems in Cell Differentiation, 53, 547–563.PubMedGoogle Scholar
  75. Lowry, K. S., Murray, S. S., McLean, C. A., Talman, P., Mathers, S., Lopes, E. C., & Cheema, S. S. (2001). A potential role for the p75 low-affinity neurotrophin receptor in spinal motor neuron degeneration in murine and human amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 2, 127–134.PubMedGoogle Scholar
  76. Lu, B. (2003). Pro-region of neurotrophins: role in synaptic modulation. Neuron, 39, 735–738.PubMedGoogle Scholar
  77. Maisonpierre, P. C., Belluscio, L., Squinto, S., Ip, N. Y., Furth, M. E., Lindsay, R. M., & Yancopoulos, G. D. (1990). Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science, 247, 1446–1451.PubMedGoogle Scholar
  78. Majdan, M., Lachance, C., Gloster, A., Aloyz, R., Zeindler, C., Bamji, S., Bhakar, A., Belliveau, D., Fawcett, J., Miller, F. D., & Barker, P. A. (1997). Transgenic mice expressing the intracellular domain of the p75 neurotrophin receptor undergo neuronal apoptosis. The Journal of Neuroscience, 17, 6988–9698.PubMedGoogle Scholar
  79. Manfredi Romanini, M. G., Fraschini, A., & Bernocchi, G. (1973). DNA content and nuclear area in the neurons of the cerebral ganglion in Helix pomatia. Annales d’Histochimie, 18, 49–58.PubMedGoogle Scholar
  80. Mi, S., Lee, X., Shao, Z., Thill, G., Ji, B., Relton, J., Levesque, M., Allaire, N., Perrin, S., Sands, B., Crowell, T., Cate, R. L., McCoy, J. M., & Pepinsky, R. B. (2004). LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nature Neuroscience, 7, 221–228.PubMedGoogle Scholar
  81. Michalski, B., & Fahnestock, M. (2003). Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer’s disease. Brain Research. Molecular Brain Research, 111, 148–154.PubMedGoogle Scholar
  82. Morillo, S. M., & Frade, J. M. (2008). Nerve growth factor signaling in neural cancer and metastasis. In G. K. McIntire (Ed.), Nerve growth factor: new research (pp. 203–227). New York: NOVA Science Publishers.Google Scholar
  83. Morillo, S. M., Escoll, P., de la Hera, A., & Frade, J. M. (2010). Somatic tetraploidy in specific chick retinal ganglion cells induced by nerve growth factor. Proceedings of the National Academy of Sciences of the United States of America, 107, 109–114.PubMedCentralPubMedGoogle Scholar
  84. Mosch, B., Morawski, M., Mittag, A., Lenz, D., Tarnok, A., & Arendt, T. (2007). Aneuploidy and DNA replication in the normal human brain and Alzheimer’s disease. The Journal of Neuroscience, 27, 6859–6867.PubMedGoogle Scholar
  85. Mukai, J., Hachiya, T., Shoji-Hoshino, S., Kimura, M. T., Nadano, D., Suvanto, P., Hanaoka, T., Li, Y., Irie, S., Greene, L. A., & Sato, T. A. (2000). NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR. The Journal of Biological Chemistry, 275, 17566–17570.PubMedGoogle Scholar
  86. Nakamura, T., Endo, K., & Kinoshita, S. (2007). Identification of human oral keratinocyte stem/progenitor cells by neurotrophin receptor p75 and the role of neurotrophin/p75 signaling. Stem Cells, 25, 628–638.PubMedGoogle Scholar
  87. Nykjaer, A., Lee, R., Teng, K. K., Jansen, P., Madsen, P., Nielsen, M. S., Jacobsen, C., Kliemannel, M., Schwarz, E., Willnow, T. E., Hempstead, B. L., & Petersen, C. M. (2004). Sortilin is essential for proNGF-induced neuronal cell death. Nature, 427, 843–848.PubMedGoogle Scholar
  88. Okano, H. J., Pfaffm, D. W., & Gibbs, R. B. (1996). Expression of EGFR-, p75NGFR-, and PSTAIRcdc2-like immunoreactivity by proliferating cells in the adult rat hippocampal formation and forebrain. Developmental Neurosciences, 18, 199–209.Google Scholar
  89. Okumura, T., Shimada, Y., Imamura, M., & Yasumoto, S. (2003). Neurotrophin receptor p75NTR characterizes human esophageal keratinocyte stem cells in vitro. Oncogene, 22, 4017–4026.PubMedGoogle Scholar
  90. Osuga, H., Osuga, S., Wang, F., Fetni, R., Hogan, M. J., Slack, R. S., Hakim, A. M., Ikeda, J.-E., & Park, D. S. (2000). Cyclin-dependent kinases as a therapeutic target for stroke. Proceedings of the National Academy of Sciences of the United States of America, 97, 10254–10259.PubMedCentralPubMedGoogle Scholar
  91. Parkhurst, C. N., Zampieri, N., & Chao, M. V. (2010). Nuclear localization of the p75 neurotrophin receptor intracellular domain. The Journal of Biological Chemistry, 285, 5361–5368.PubMedCentralPubMedGoogle Scholar
  92. Pelegrí, C., Duran-Vilaregut, J., del Valle, J., Crespo-Biel, N., Ferrer, I., Pallàs, M., Camins, A., & Vilaplana, J. (2008). Cell cycle activation in striatal neurons from Huntington’s disease patients and rats treated with 3-nitropropionic acid. International Journal of Developmental Neuroscience, 26, 665–671.PubMedGoogle Scholar
  93. Pincheira, R., Baerwald, M., Dunbar, J. D., & Donner, D. B. (2009). Sall2 is a novel p75NTR-interacting protein that links NGF signalling to cell cycle progression and neurite outgrowth. The EMBO Journal, 28, 261–273.PubMedCentralPubMedGoogle Scholar
  94. Podlesniy, P., Kichev, A., Pedraza, C., Saurat, J., Encinas, M., Perez, B., Ferrer, I., & Espinet, C. (2006). Pro-NGF from Alzheimer’s disease and normal human brain displays distinctive abilities to induce processing and nuclear translocation of intracellular domain of p75NTR and apoptosis. The American Journal of Pathology, 169, 119–131.PubMedCentralPubMedGoogle Scholar
  95. Radeke, M. J., Misko, T. P., Hsu, C., Herzenberg, L. A., & Shooter, E. M. (1987). Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature, 325, 593–597.PubMedGoogle Scholar
  96. Ranganathan, S., & Bowser, R. (2003). Alterations in G1 to S phase cell-cycle regulators during amyotrophic lateral sclerosis. The American Journal of Pathology, 162, 823–835.PubMedCentralPubMedGoogle Scholar
  97. Ranganathan, S., & Bowser, R. (2010). p53 and cell cycle proteins participate in spinal motor neuron cell death in ALS. The Open Pathology Journal, 4, 11–22.PubMedCentralPubMedGoogle Scholar
  98. Reynolds, B. A., & Weiss, S. (1992). Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science, 255, 1707–1710.PubMedGoogle Scholar
  99. Rodríguez-Tébar, A., Dechant, G., & Barde, Y. A. (1990). Binding of brain-derived neurotrophic factor to the nerve growth factor receptor. Neuron, 4, 487–492.PubMedGoogle Scholar
  100. Rodríguez-Tébar, A., Dechant, G., Götz, R., & Barde, Y. A. (1992). Binding of neurotrophin-3 to its neuronal receptors and interactions with nerve growth factor and brain-derived neurotrophic factor. The EMBO Journal, 11, 917–922.PubMedCentralPubMedGoogle Scholar
  101. Rosenthal, A., Goeddel, D. V., Nguyen, T., Lewis, M., Shih, A., Laramee, G. R., Nikolics, K., & Winslow, J. W. (1990). Primary structure and biological activity of a novel human neurotrophic factor. Neuron, 4, 767–773.PubMedGoogle Scholar
  102. Salehi, A. H., Roux, P. P., Kubu, C. J., Zeindler, C., Bhakar, A., Tannis, L. L., Verdi, J. M., & Barker, P. A. (2000). NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis. Neuron, 27, 279–288.PubMedGoogle Scholar
  103. Skeldal, S., Matusica, D., Nykjaer, A., & Coulson, E. J. (2011). Proteolytic processing of the p75 neurotrophin receptor: a prerequisite for signalling?: Neuronal life, growth and death signalling are crucially regulated by intra-membrane proteolysis and trafficking of p75(NTR). Bioessays, 33, 614–625.PubMedGoogle Scholar
  104. Sotthibundhu, A., Li, Q. X., Thangnipon, W., & Coulson, E. J. (2009). Aβ1-42 stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor. Neurobiology of Aging, 30, 1975–1985.PubMedGoogle Scholar
  105. Stone, J. G., Siedlak, S. L., Tabaton, M., Hirano, A., Castellani, R. J., Santocanale, C., Perry, G., Smith, M. A., Zhu, X., & Lee, H. G. (2011). The cell cycle regulator phosphorylated retinoblastoma protein is associated with tau pathology in several tauopathies. Journal of Neuropathology and Experimental Neurology, 70, 578–587.PubMedCentralPubMedGoogle Scholar
  106. Susen, K., Heumann, R., & Blöchl, A. (1999). Nerve growth factor stimulates MAPK via the low affinity receptor p75LNTR. FEBS Letters, 463, 231–234.PubMedGoogle Scholar
  107. Swartz, F. J., & Bhatnagar, K. P. (1981). Are CNS neurons polyploid? A critical analysis based upon cytophotometric study of the DNA content of cerebellar and olfactory bulbar neurons of the bat. Brain Research, 208, 267–281.PubMedGoogle Scholar
  108. Swift, H. (1953). Quantitative aspects of nuclear nucleoproteins. International Review of Cytology, 2, 1–76.Google Scholar
  109. Szaro, B. G., & Tompkins, R. (1987). Effect of tetraploidy on dendritic branching in neurons and glial cells of the frog, Xenopus laevis. The Journal of Comparative Neurology, 258, 304–316.PubMedGoogle Scholar
  110. Taniura, H., Taniguchi, N., Hara, M., & Yoshikawa, K. (1998). Necdin, a postmitotic neuron-specific growth suppressor, interacts with viral transforming proteins and cellular transcription factor E2F1. The Journal of Biological Chemistry, 273, 720–728.PubMedGoogle Scholar
  111. Tcherpakov, M., Bronfman, F. C., Conticello, S. G., Vaskovsky, A., Levy, Z., Niinobe, M., Yoshikawa, K., Arenas, E., & Fainzilber, M. (2002). The p75 neurotrophin receptor interacts with multiple MAGE proteins. The Journal of Biological Chemistry, 277, 49101–49104.PubMedGoogle Scholar
  112. Teng, H. K., Teng, K. K., Lee, R., Wright, S., Tevar, S., Almeida, R. D., Kermani, P., Torkin, R., Chen, Z. Y., Lee, F. S., Kraemer, R. T., Nykjaer, A., & Hempstead, B. L. (2005). ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. The Journal of Neuroscience, 25, 5455–5463.PubMedGoogle Scholar
  113. Ullah, Z., Lee, C. Y., Lilly, M. A., & DePamphilis, M. L. (2009). Developmentally programmed endoreduplication in animals. Cell Cycle, 8, 1501–1509.PubMedCentralPubMedGoogle Scholar
  114. Urdiales, J. L., Becker, E., Andrieu, M., Thomas, A., Jullien, J., van Grunsven, L. A., Menut, S., Evan, G. I., Martín-Zanca, D., & Rudkin, B. B. (1998). Cell cycle phase-specific surface expression of nerve growth factor receptors TrkA and p75NTR. The Journal of Neuroscience, 18, 6767–6775.PubMedGoogle Scholar
  115. Veeriah, S., Morris, L., Solit, D., & Chan, T. A. (2010). The familial Parkinson disease gene PARK2 is a multisite tumor suppressor on chromosome 6q25.2-27 that regulates cyclin E. Cell Cycle, 9, 1451–1452.PubMedCentralPubMedGoogle Scholar
  116. Verbeke, S., Meignan, S., Lagadec, C., Germain, E., Hondermarck, H., Adriaenssens, E., & Le Bourhis, X. (2010). Overexpression of p75NTR increases survival of breast cancer cells through p21waf1. Cellular Signalling, 22, 1864–1873.PubMedGoogle Scholar
  117. Verdaguer, E., Jiménez, A., Canudas, A. M., Jordà, E. G., Sureda, F. X., Pallàs, M., & Camins, A. (2004). Inhibition of cell cycle pathway by flavopiridol promotes survival of cerebellar granule cells after an excitotoxic treatment. The Journal of Pharmacology and Experimental Therapeutics, 308, 609–616.PubMedGoogle Scholar
  118. Vilar, M., Murillo-Carretero, M., Mira, H., Magnusson, K., Besset, V., & Ibáñez, C. F. (2006). Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle. The EMBO Journal, 25, 1219–1230.PubMedCentralPubMedGoogle Scholar
  119. Volosin, M., Trotter, C., Cragnolini, A., Kenchappa, R. S., Light, M., Hempstead, B. L., Carter, B. D., & Friedman, W. J. (2008). Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures. The Journal of Neuroscience, 28, 9870–9879.PubMedCentralPubMedGoogle Scholar
  120. Wang, K. C., Kimm, J. A., Sivasankaran, R., Segal, R., & He, Z. (2002). p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature, 420, 74–78.PubMedGoogle Scholar
  121. Wang, W., Bu, B., Xie, M., Zhang, M., Yu, Z., & Tao, D. (2009). Neural cell cycle dysregulation and central nervous system diseases. Progress in Neurobiology, 89, 1–17.PubMedGoogle Scholar
  122. Wen, C. J., Xue, B., Qin, W. X., Yu, M., Zhang, M. Y., Zhao, D. H., Gao, X., Gu, J. R., & Li, C. J. (2004). hNRAGE, a human neurotrophin receptor interacting MAGE homologue, regulates p53 transcriptional activity and inhibits cell proliferation. FEBS Letters, 564, 171–176.PubMedGoogle Scholar
  123. Woo, N. H., Teng, H. K., Siao, C. J., Chiaruttini, C., Pang, P. T., Milner, T. A., Hempstead, B. L., & Lu, B. (2005). Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nature Neuroscience, 8, 1069–1077.PubMedGoogle Scholar
  124. Woods, J., Snape, M., & Smith, M. A. (2007). The cell cycle hypothesis of Alzheimer’s disease: suggestions for drug development. Biochimica et Biophysica Acta, 1772, 503–508.PubMedGoogle Scholar
  125. Yang, Y., Geldmacher, D. S., & Herrup, K. (2001). DNA replication precedes neuronal cell death in Alzheimer’s disease. The Journal of Neuroscience, 21, 2661–2668.PubMedGoogle Scholar
  126. Yankner, B. A., & Shooter, E. M. (1982). The biology and mechanism of action of nerve growth factor. Annual Review of Biochemistry, 51, 845–868.PubMedGoogle Scholar
  127. Yano, H., Torkin, R., Martin, L. A., Chao, M. V., & Teng, K. K. (2009). Proneurotrophin-3 is a neuronal apoptotic ligand: evidence for retrograde-directed cell killing. The Journal of Neuroscience, 29, 14790–14802.PubMedCentralPubMedGoogle Scholar
  128. Young, K. M., Mersonm, T. D., Sotthibundhum, A., Coulson, E. J., & Bartlett, P. F. (2007). p75 neurotrophin receptor expression defines a population of BDNF-responsive neurogenic precursor cells. The Journal of Neuroscience, 27, 5146–5155.PubMedGoogle Scholar
  129. Yuanlong, H., Haifeng, J., Xiaoyin, Z., Jialin, S., Jie, L., Li, Y., Huahong, X., Jiugang, S., Yanglin, P., Kaichun, W., Jie, D., & Daiming, F. (2008). The inhibitory effect of p75 neurotrophin receptor on growth of human hepatocellular carcinoma cells. Cancer Letters, 268, 110–119.PubMedGoogle Scholar
  130. Zhang, W., & Liu, H. T. (2002). MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Research, 12, 9–18.PubMedGoogle Scholar
  131. Zhang, W., Zeng, Y. S., Wang, J. M., Ding, Y., Li, Y., & Wu, W. (2009). Neurotrophin-3 improves retinoic acid-induced neural differentiation of skin-derived precursors through a p75NTR-dependent signaling pathway. Neuroscience Research, 64, 170–176.PubMedGoogle Scholar
  132. Zhu, W., Cheng, S., Xu, G., Ma, M., Zhou, Z., Liu, D., & Liu, X. (2011). Intranasal nerve growth factor enhances striatal neurogenesis in adult rats with focal cerebral ischemia. Drug Delivery, 18, 338–343.PubMedGoogle Scholar
  133. Zuccato, C., Marullo, M., Conforti, P., MacDonald, M. E., Tartari, M., & Cattaneo, E. (2008). Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington’s disease. Brain Pathology, 18, 225–238.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Noelia López-Sánchez
    • 1
  • María Carmen Ovejero-Benito
    • 1
  • Claudia Rodríguez-Ruiz
    • 1
  • José María Frade
    • 1
  1. 1.Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC)MadridSpain

Personalised recommendations