Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cell cycle regulation in the postmitotic neuron: oxymoron or new biology?

Key Points

  • The review examines the current state of knowledge concerning the regulation of the cell cycle in the CNS during development and in the adult. Several key points emerge from the assembled evidence.

  • Neurons must constantly suppress the cell cycle once they complete neurogenesis. If they fail to do so they will re-enter a cell cycle that they will not be able to complete.

  • These 'cycling' neurons seem to be consigned to one of two fates depending on their stage of maturation: in young differentiating neurons, re-entry into a cell cycle leads to death within hours, which can be blocked by inhibition of the cell cycle. In adult neurons, re-entry into a cell cycle leads to the expression of cell cycle proteins and replication of some or all of the genome, but for many months the neurons appear incapable of either completing the cycle or dying.

  • The linkage between cell cycle and cell death appears to lie at the root of many human neurodegenerative diseases.

  • The neuron uses a multi-tiered strategy to suppress the cell cycle: there is strong evidence for genomic rearrangements, cell cycle proteins are found in unexpected locations and proteins switch from functioning as cell cycle promoters to acting as cell cycle suppressors.

  • Many proteins originally identified for their role in cell cycle progression seem to perform essential functions in the neuronal cytoplasm and, in particular, at the synapse.

Abstract

Adult CNS neurons are typically described as permanently postmitotic but there is probably nothing permanent about the neuronal cell cycle arrest. Rather, it appears that these highly differentiated cells must constantly keep their cell cycle in check. Relaxation of this vigilance leads to the initiation of a cell cycle and entrance into an altered and vulnerable state, often leading to death. There is evidence that neurons which are at risk of neurodegeneration are also at risk of re-initiating a cell cycle process that involves the expression of cell cycle proteins and DNA replication. Failure of cell cycle regulation might be a root cause of several neurodegenerative disorders and a final common pathway for others.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The developing cerebral cortex.
Figure 2: Cell cycle proteins implicated in each of the three phases of neuronal development.
Figure 3: Mature and immature neurons differ in their response to cell cycle initiation.
Figure 4: Speculative model of how a 'cycling' neuron might be a threat to the health of the CNS.

References

  1. Cai, L., Hayes, N. L. & Nowakowski, R. S. Synchrony of clonal cell proliferation and contiguity of clonally related cells: production of mosaicism in the ventricular zone of developing mouse neocortex. J. Neurosci. 17, 2088–2100 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cai, L., Hayes, N. L. & Nowakowski, R. S. Local homogeneity of cell cycle length in developing mouse cortex. J. Neurosci. 17, 2079–2087 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Takahashi, T., Goto, T., Miyama, S., Nowakowski, R. S. & Caviness, V. S. Jr. Sequence of neuron origin and neocortical laminar fate: relation to cell cycle of origin in the developing murine cerebral wall. J. Neurosci. 19, 10357–10371 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Takahashi, T., Nowakowski, R. S. & Caviness, V. S. Jr. The cell cycle of the pseudostratified ventricular epithelium of the embryonic murine cerebral wall. J. Neurosci. 15, 6046–6057 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Takahashi, T., Nowakowski, R. S. & Caviness, V. S. Jr. Cell cycle parameters and patterns of nuclear movement in the neocortical proliferative zone of the fetal mouse. J. Neurosci. 13, 820–833 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Miale, I. L. & Sidman, R. L. An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp. Neurol. 4, 277–296 (1961).

    Article  CAS  PubMed  Google Scholar 

  7. Uzman, L. L. The histogenesis of the mouse cerebellum as studied by its tritiated thymidine uptake. J. Comp. Neurol. 114, 137–159 (1960).

    Article  CAS  PubMed  Google Scholar 

  8. Nowakowski, R. S., Lewin, S. B. & Miller, M. W. Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population. J. Neurocyt. 18, 311–318 (1989).

    Article  CAS  Google Scholar 

  9. Bonnert, T. P. et al. Molecular characterization of adult mouse subventricular zone progenitor cells during the onset of differentiation. Eur. J. Neurosci. 24, 661–675 (2006).

    Article  PubMed  Google Scholar 

  10. Noctor, S. C., Martinez-Cerdeno, V., Ivic, L. & Kriegstein, A. R. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nature Neurosci. 7, 136–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Taupin, P. Neurogenesis in the adult central nervous system. C. R. Biol. 329, 465–475 (2006).

    Article  PubMed  Google Scholar 

  12. Sohur, U. S., Emsley, J. G., Mitchell, B. D. & Macklis, J. D. Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 361, 1477–1497 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Aimone, J. B., Wiles, J. & Gage, F. H. Potential role for adult neurogenesis in the encoding of time in new memories. Nature Neurosci. 9, 723–727 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Kuan, C. Y. et al. Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. J. Neurosci. 24, 10763–10772 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kenney, A. M., Cole, M. D. & Rowitch, D. H. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130, 15–28 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Ruiz i Altaba, A., Palma, V. & Dahmane, N. Hedgehog–Gli signalling and the growth of the brain. Nature Rev. Neurosci. 3, 24–33 (2002).

    Article  CAS  Google Scholar 

  17. Clarke, A. R. et al. Requirement for a functional Rb-1 gene in murine development. Nature 359, 328–330 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Lee, E. Y. et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359, 288–294 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Lee, E. Y. et al. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev. 8, 2008–2021 (1994). A detailed description of how a cell cycle protein can also be a potent pro-differentiation agent.

    Article  CAS  PubMed  Google Scholar 

  21. Cunningham, J. J. & Roussel, M. F. Cyclin-dependent kinase inhibitors in the development of the central nervous system. Cell Growth Differ. 12, 387–396 (2001).

    CAS  PubMed  Google Scholar 

  22. Cunningham, J. J. et al. The cyclin-dependent kinase inhibitors p19Ink4d and p27Kip1 are coexpressed in select retinal cells and act cooperatively to control cell cycle exit. Mol. Cell. Neurosci. 19, 359–374 (2002). A clear demonstration of how certain CKIs assist in the orderly cessation of neuronal cell division.

    Article  CAS  PubMed  Google Scholar 

  23. Schmetsdorf, S., Gartner, U. & Arendt, T. Expression of cell cycle-related proteins in developing and adult mouse hippocampus. Int. J. Dev. Neurosci. 23, 101–112 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Blackshaw, S. et al. Genomic analysis of mouse retinal development. PLoS Biol. 2, E247 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Dehay, C., Savatier, P., Cortay, V. & Kennedy, H. Cell-cycle kinetics of neocortical precursors are influenced by embryonic thalamic axons. J. Neurosci. 21, 201–214 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lukaszewicz, A. et al. G1 phase regulation, area-specific cell cycle control, and cytoarchitectonics in the primate cortex. Neuron 47, 353–364 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gao, Y. et al. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95, 891–902 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Barnes, D. E., Stamp, G., Rosewell, I., Denzel, A. & Lindahl, T. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr. Biol. 8, 1395–1398 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Esposito, G. et al. Mice reconstituted with DNA polymerase β-deficient fetal liver cells are able to mount a T cell-dependent immune response and mutate their Ig genes normally. Proc. Natl Acad. Sci. USA 97, 1166–1171 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sugo, N., Aratani, Y., Nagashima, Y., Kubota, Y. & Koyama, H. Neonatal lethality with abnormal neurogenesis in mice deficient in DNA polymerase β. EMBO J. 19, 1397–1404 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee, Y., Barnes, D. E., Lindahl, T. & McKinnon, P. J. Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev. 14, 2576–2580 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chun, J. Cell death, DNA breaks and possible rearrangements: an alternative view. Trends Neurosci. 23, 407–409 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Gilmore, E. C., Herrup, K., Nowakowski, R. S. & Caviness, V. S. Jr. Reply. Trends Neurosci. 23, 408–409 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Gilmore, E. C., Nowakowski, R. S., Caviness, V. S. Jr. & Herrup, K. Cell birth, cell death, cell diversity and DNA breaks: how do they all fit together? Trends Neurosci. 23, 100–105 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Baker, S. J. & McKinnon, P. J. Tumour-suppressor function in the nervous system. Nature Rev. Cancer 4, 184–196 (2004).

    Article  CAS  Google Scholar 

  36. O'Driscoll, M. & Jeggo, P. A. The role of double-strand break repair- insights from human genetics. Nature Rev. Genet. 7, 45–54 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Murphy, M. et al. Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nature Genet. 15, 83–86 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Brandeis, M. et al. Cyclin B2-null mice develop normally and are fertile whereas cyclin B1-null mice die in utero. Proc. Natl Acad. Sci. USA 95, 4344–4349 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kozar, K. et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118, 477–491 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Levine, E. M., Close, J., Fero, M., Ostrovsky, A. & Reh, T. A. p27Kip1 regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina. Dev. Biol. 219, 299–314 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Mitsuhashi, T. et al. Overexpression of p27Kip1 lengthens the G1 phase in a mouse model that targets inducible gene expression to central nervous system progenitor cells. Proc. Natl Acad. Sci. USA 98, 6435–6440 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ciemerych, M. A. & Sicinski, P. Cell cycle in mouse development. Oncogene 24, 2877–2898 (2005). This is a comprehensive yet readable overview of virtually every cell cycle gene knockout in mice.

    Article  CAS  PubMed  Google Scholar 

  43. al-Ubaidi, M. R., Hollyfield, J. G., Overbeek, P. A. & Baehr, W. Photoreceptor degeneration induced by the expression of simian virus 40 large tumor antigen in the retina of transgenic mice. Proc. Natl Acad. Sci. USA 89, 1194–1198 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Feddersen, R. M., Clark, H. B., Yunis, W. S. & Orr, H. T. In vivo viability of postmitotic Purkinje neurons requires pRb family member function. Mol. Cell. Neurosci. 6, 153–167 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Feddersen, R. M., Ehlenfeldt, R., Yunis, W. S., Clark, H. B. & Orr, H. T. Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice. Neuron 9, 955–966 (1992). The earliest demonstration (see also references 44 and 46) that driving a cell cycle in a postmitotic neuron triggers death rather than division.

    Article  CAS  PubMed  Google Scholar 

  46. Feddersen, R. M. et al. Susceptibility to cell death induced by mutant SV40 T-antigen correlates with Purkinje neuron functional development. Mol. Cell. Neurosci. 9, 42–62 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Athanasiou, M. C. et al. The transcription factor E2F-1 in SV40 T antigen-induced cerebellar Purkinje cell degeneration. Mol. Cell. Neurosci. 12, 16–28 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Macleod, K. F., Hu, Y. & Jacks, T. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. EMBO J. 15, 6178–6188 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tsai, K. Y. et al. Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol. Cell 2, 293–304 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Freeman, R. S., Estus, S. & Johnson, E. M. Jr. Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of Cyclin D1 during programmed cell death. Neuron 12, 343–355 (1994).

    Article  CAS  PubMed  Google Scholar 

  51. Herrup, K. & Busser, J. C. The induction of multiple cell cycle events precedes target-related neuronal death. Development 121, 2385–2395 (1995). The first demonstration that natural examples of developmental cell death are preceded by cell cycle activation.

    Article  CAS  PubMed  Google Scholar 

  52. Farinelli, S. E. & Greene, L. A. Cell cycle blockers mimosine, ciclopirox, and deferoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support. J. Neurosci. 16, 1150–1162 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Park, D. S., Levine, B., Ferrari, G. & Greene, L. A. Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase 4 and 6 promote survival of NGF-deprived sympathetic neurons. J. Neurosci. 17, 8975–8983 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Park, D. S., Morris, E. J., Greene, L. A. & Geller, H. M. G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis. J. Neurosci. 17, 1256–1270 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Park, D. S., Farinelli, S. E. & Greene, L. A. Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons. J. Biol. Chem. 271, 8161–8169 (1996).

    Article  PubMed  Google Scholar 

  56. Ferrari, G. & Greene, L. A. Proliferative inhibition by dominant-negative Ras rescues naive and neuronally differentiated PC12 cells from apoptotic death. EMBO J. 13, 5922–5928 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Park, D. S., Obeidat, A., Giovanni, A. & Greene, L. A. Cell cycle regulators in neuronal death evoked by excitotoxic stress: implications for neurodegeneration and its treatment. Neurobiol. Aging 21, 771–781 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Courtney, M. J. & Coffey, E. T. The mechanism of Ara-C-induced apoptosis of differentiating cerebellar granule neurons. Eur. J. Neurosci. 11, 1073–1084 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Mirjany, M., Ho, L. & Pasinetti, G. M. Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity. J. Pharmacol. Exp. Ther. 301, 494–500 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Padmanabhan, J., Park, D. S., Greene, L. A. & Shelanski, M. L. Role of cell cycle regulatory proteins in cerebellar granule neuron apoptosis. J. Neurosci. 19, 8747–8756 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Liu, D. X., Biswas, S. C. & Greene, L. A. B-myb and C-myb play required roles in neuronal apoptosis evoked by nerve growth factor deprivation and DNA damage. J. Neurosci. 24, 8720–8725 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Biswas, S. C., Liu, D. X. & Greene, L. A. Bim is a direct target of a neuronal E2F-dependent apoptotic pathway. J. Neurosci. 25, 8349–8358 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Konishi, Y. & Bonni, A. The E2F-Cdc2 cell-cycle pathway specifically mediates activity deprivation-induced apoptosis of postmitotic neurons. J. Neurosci. 23, 1649–1658 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Konishi, Y., Lehtinen, M., Donovan, N. & Bonni, A. Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol. Cell 9, 1005–1016 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Lipinski, M. M. et al. Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous system. EMBO J. 20, 3402–3413 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Maandag, E. C. et al. Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. EMBO J. 13, 4260–4268 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Williams, B. O. et al. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. EMBO J. 13, 4251–4259 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. MacPherson, D. et al. Conditional mutation of Rb causes cell cycle defects without apoptosis in the central nervous system. Mol. Cell Biol. 23, 1044–1053 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wu, L. et al. Extra-embryonic function of Rb is essential for embryonic development and viability. Nature 421, 942–947 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. De Bruin, A. et al. Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb-deficient mice. Proc. Natl Acad. Sci. USA 100, 6546–6551 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vincent, I., Rosado, M. & Davies, P. Mitotic mechanisms in Alzheimer's disease? J. Cell Biol. 132, 413–425 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Vincent, I., Zheng, J. H., Dickson, D. W., Kress, Y. & Davies, P. Mitotic phosphoepitopes precede paired helical filaments in Alzheimer's disease. Neurobiol. Aging 19, 287–296 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Nagy, Z., Esiri, M., Cato, A. & Smith, A. Cell cycle markers in the hippocampus in Alzheimer's disease. Acta Neuropathol. (Berl) 94, 6–15 (1997).

    Article  CAS  Google Scholar 

  74. Busser, J., Geldmacher, D. S. & Herrup, K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J. Neurosci. 18, 2801–2807 (1998). The first demonstration that cell cycle events in human neurodegenerative disease are accompanied by DNA replication.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yang, Y., Geldmacher, D. S. & Herrup, K. DNA replication precedes neuronal cell death in Alzheimer's disease. J. Neurosci. 21, 2661–2668 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yang, Y., Mufson, E. J. & Herrup, K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J. Neurosci. 23, 2557–2563 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Arendt, T., Holzer, M. & Gartner, U. Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer's disease. J. Neural Transm. 105, 949–960 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. Hoozemans, J. J. et al. Cyclin D1 and cyclin E are co-localized with cyclo-oxygenase 2 (COX-2) in pyramidal neurons in Alzheimer disease temporal cortex. J. Neuropathol. Exp. Neurol. 61, 678–688 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. McShea, A., Harris, P. L., Webster, K. R., Wahl, A. F. & Smith, M. A. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am. J. Pathol. 150, 1933–1939 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Vincent, I., Jicha, G., Rosado, M. & Dickson, D. W. Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J. Neurosci. 17, 3588–3598 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Smith, M. Z., Nagy, Z. & Esiri, M. M. Cell cycle-related protein expression in vascular dementia and Alzheimer's disease. Neurosci. Lett. 271, 45–48 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Arendt, T., Rodel, L., Gartner, U. & Holzer, M. Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer's disease. Neuroreport 7, 3047–3049 (1996).

    Article  CAS  PubMed  Google Scholar 

  83. Zhu, X. et al. Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP-1-associated regulator of cyclin B, in Alzheimer's disease. J. Neurosci. Res. 75, 698–703 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Johansson, A. et al. Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 20, 367–374 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Johansson, A. et al. Increased frequency of a new polymorphism in the cell division cycle 2 (cdc2) gene in patients with Alzheimer's disease and frontotemporal dementia. Neurosci. Lett. 340, 69–73 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Nguyen, M. D. et al. Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J. Neurosci. 23, 2131–2140 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ranganathan, S. & Bowser, R. Alterations in G1 to S phase cell-cycle regulators during amyotrophic lateral sclerosis. Am. J. Pathol. 162, 823–835 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ranganathan, S., Scudiere, S. & Bowser, R. Hyperphosphorylation of the retinoblastoma gene product and altered subcellular distribution of E2F-1 during Alzheimer's disease and amyotrophic lateral sclerosis. J. Alzheimers Dis. 3, 377–385 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Yang, Y. & Herrup, K. Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J. Neurosci. 25, 2522–2529 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Burns, K. A. et al. Nestin-CreER mice reveal DNA synthesis by nonapoptotic neurons following cerebral ischemia-hypoxia. Cereb. Cortex 27 Jan 2007 (doi:10.1093/cercor/bhl164).

    Article  PubMed  Google Scholar 

  91. Höglinger, G. et al. The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease. Proc. Natl Acad. Sci. USA 104, 3585–3590 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Jordan-Sciutto, K. L., Dorsey, R., Chalovich, E. M., Hammond, R. R. & Achim, C. L. Expression patterns of retinoblastoma protein in Parkinson disease. J. Neuropathol. Exp. Neurol. 62, 68–74 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. West, A. B., Dawson, V. L. & Dawson, T. M. To die or grow: Parkinson's disease and cancer. Trends Neurosci. 28, 348–352 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Love, S. Neuronal expression of cell cycle-related proteins after brain ischaemia in man. Neurosci. Lett. 353, 29–32 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Jordan-Sciutto, K. L., Wang, G., Murphey-Corb, M. & Wiley, C. A. Cell cycle proteins exhibit altered expression patterns in lentiviral-associated encephalitis. J. Neurosci. 22, 2185–2195 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jordan-Sciutto, K. L., Wang, G., Murphy-Corb, M. & Wiley, C. A. Induction of cell-cycle regulators in simian immunodeficiency virus encephalitis. Am. J. Pathol. 157, 497–507 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Borghesani, P. R. et al. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc. Natl Acad. Sci. USA 97, 3336–3341 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996).

    Article  CAS  PubMed  Google Scholar 

  100. Lamb, B. T. et al. Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice. Nature Genet. 5, 22–30 (1993).

    Article  CAS  PubMed  Google Scholar 

  101. Hsiao, K. K. et al. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15, 1203–1218 (1995).

    Article  CAS  PubMed  Google Scholar 

  102. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527 (1995).

    Article  CAS  PubMed  Google Scholar 

  104. Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl Acad. Sci. USA 94, 13287–13292 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mucke, L. et al. High-level neuronal expression of aβ 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Citron, M. et al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature Med. 3, 67–72 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Calhoun, M. E. et al. Neuron loss in APP transgenic mice. Nature 395, 755–756 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Barlow, C. et al. ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation. Proc. Natl Acad. Sci. USA 97, 871–876 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hock, B. J. Jr. & Lamb, B. T. Transgenic mouse models of Alzheimer's disease. Trends Genet. 17, S7–S12 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Yang, Y., Varvel, N. H., Lamb, B. T. & Herrup, K. Ectopic cell cycle events link human Alzheimer's disease and amyloid precursor protein transgenic mouse models. J. Neurosci. 26, 775–784 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gartner, U. et al. Amyloid deposition in APP23 mice is associated with the expression of cyclins in astrocytes but not in neurons. Acta Neuropathol. (Berl) 106, 535–544 (2003).

    Article  CAS  Google Scholar 

  112. Jordan-Sciutto, K., Rhodes, J. & Bowser, R. Altered subcellular distribution of transcriptional regulators in response to Aβ peptide and during Alzheimer's disease. Mech. Ageing Dev. 123, 11–20 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Jordan-Sciutto, K. L., Murray Fenner, B. A., Wiley, C. A. & Achim, C. L. Response of cell cycle proteins to neurotrophic factor and chemokine stimulation in human neuroglia. Exp. Neurol. 167, 205–214 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Strachan, G. D., Kopp, A. S., Koike, M. A., Morgan, K. L. & Jordan-Sciutto, K. L. Chemokine- and neurotrophic factor-induced changes in E2F1 localization and phosphorylation of the retinoblastoma susceptibility gene product (pRb) occur by distinct mechanisms in murine cortical cultures. Exp. Neurol. 193, 455–468 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Delalle, I., Takahashi, T., Nowakowski, R. S., Tsai, L. H. & Caviness, V. S. Jr. Cyclin E-p27 opposition and regulation of the G1 phase of the cell cycle in the murine neocortical PVE: a quantitative analysis of mRNA in situ hybridization. Cereb. Cortex 9, 824–832 (1999). A detailed look at the effects on cell cycle kinetics of the elimination of a key CDK inhibitor, p27.

    Article  CAS  PubMed  Google Scholar 

  116. Dyer, M. A. & Cepko, C. L. p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations. J. Neurosci. 21, 4259–4271 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dyer, M. A. & Cepko, C. L. p57Kip2 regulates progenitor cell proliferation and amacrine interneuron development in the mouse retina. Development 127, 3593–3605 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Gui, H., Li, S. & Matise, M. P. A cell-autonomous requirement for Cip/Kip cyclin-kinase inhibitors in regulating neuronal cell cycle exit but not differentiation in the developing spinal cord. Dev. Biol. 301, 14–26 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Nguyen, L. et al. p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes Dev. 20, 1511–1524 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Cicero, S. & Herrup, K. Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J. Neurosci. 25, 9658–9668 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Rosales, J. L., Nodwell, M. J., Johnston, R. N. & Lee, K. Y. Cdk5/p25nck5a interaction with synaptic proteins in bovine brain. J. Cell Biochem. 78, 151–159 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Fu, A. K. et al. Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nature Neurosci. 4, 374–381 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Fu, A. K. et al. Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice. Proc. Natl Acad. Sci. USA 102, 15224–15229 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Fu, W. Y. et al. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nature Neurosci. 10, 67–76 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Lee, S. Y., Wenk, M. R., Kim, Y., Nairn, A. C. & De Camilli, P. Regulation of synaptojanin 1 by cyclin-dependent kinase 5 at synapses. Proc. Natl Acad. Sci. USA 101, 546–551 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Morabito, M. A., Sheng, M. & Tsai, L. H. Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J. Neurosci. 24, 865–876 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Tomizawa, K. et al. Cophosphorylation of amphiphysin I and dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles. J. Cell Biol. 163, 813–824 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Huang, Z., Zang, K. & Reichardt, L. F. The origin recognition core complex regulates dendrite and spine development in postmitotic neurons. J. Cell Biol. 170, 527–535 (2005). Analysis of the unexplained presence of proteins normally associated with DNA replication biochemistry in the mature neuronal synapse.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Thome, K. C. et al. Subsets of human origin recognition complex (ORC) subunits are expressed in non-proliferating cells and associate with non-ORC proteins. J. Biol. Chem. 275, 35233–35241 (2000).

    Article  CAS  PubMed  Google Scholar 

  130. Buss, R. R. & Oppenheim, R. W. Role of programmed cell death in normal neuronal development and function. Anat. Sci. Int. 79, 191–197 (2004).

    Article  PubMed  Google Scholar 

  131. Perez-Garijo, A., Martin, F. A. & Morata, G. Caspase inhibition during apoptosis causes abnormal signalling and developmental aberrations in Drosophila. Development 131, 5591–5598 (2004). 'Undead' cells signal with mitogens to neighbouring cells; the authors take a first pass at identifying the signalling molecules involved.

    Article  CAS  PubMed  Google Scholar 

  132. Perez-Garijo, A., Martin, F. A., Struhl, G. & Morata, G. Dpp signaling and the induction of neoplastic tumors by caspase-inhibited apoptotic cells in Drosophila. Proc. Natl Acad. Sci. USA 102, 17664–17669 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Huh, J. R., Guo, M. & Hay, B. A. Compensatory proliferation induced by cell death in the Drosophila wing disc requires activity of the apical cell death caspase Dronc in a nonapoptotic role. Curr. Biol. 14, 1262–1266 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Field, S. J. et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549–561 (1996).

    Article  CAS  PubMed  Google Scholar 

  135. Yamasaki, L. et al. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85, 537–548 (1996).

    Article  CAS  PubMed  Google Scholar 

  136. McKinnon, P. J. ATM and ataxia telangiectasia. EMBO Rep. 5, 772–776 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Shiloh, Y. & Kastan, M. B. ATM: genome stability, neuronal development, and cancer cross paths. Adv. Cancer Res. 83, 209–254 (2001).

    Article  CAS  PubMed  Google Scholar 

  138. Kastan, M. B. & Lim, D. S. The many substrates and functions of ATM. Nature Rev. Mol. Cell Biol. 1, 179–186 (2000).

    Article  CAS  Google Scholar 

  139. Gilmore, E. C., Ohshima, T., Goffinet, A. M., Kulkarni, A. B. & Herrup, K. Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex. J. Neurosci. 18, 6370–6377 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Ohshima, T. et al. Migration defects of cdk5−/− neurons in the developing cerebellum is cell autonomous. J. Neurosci. 19, 6017–6026 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ohshima, T. et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl Acad. Sci. USA 93, 11173–11178 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. O'Hare, M. J. et al. Differential roles of nuclear and cytoplasmic cyclin-dependent kinase 5 in apoptotic and excitotoxic neuronal death. J. Neurosci. 25, 8954–8966 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Fantl, V., Stamp, G., Andrews, A., Rosewell, I. & Dickson, C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 9, 2364–2372 (1995).

    Article  CAS  PubMed  Google Scholar 

  144. Sicinski, P. et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82, 621–630 (1995).

    Article  CAS  PubMed  Google Scholar 

  145. Sicinski, P. et al. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384, 470–474 (1996).

    Article  CAS  PubMed  Google Scholar 

  146. Huard, J. M., Forster, C. C., Carter, M. L., Sicinski, P. & Ross, M. E. Cerebellar histogenesis is disturbed in mice lacking cyclin D2. Development 126, 1927–1935 (1999).

    Article  CAS  PubMed  Google Scholar 

  147. Georgia, S. & Bhushan, A. β cell replication is the primary mechanism for maintaining postnatal β cell mass. J. Clin. Invest. 114, 963–968 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ciemerych, M. A. et al. Development of mice expressing a single D-type cyclin. Genes Dev. 16, 3277–3289 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lee, M. H. et al. Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev. 10, 1621–1632 (1996).

    Article  CAS  PubMed  Google Scholar 

  150. Eilam, R. et al. Selective loss of dopaminergic nigro-striatal neurons in brains of Atm-deficient mice. Proc. Natl Acad. Sci. USA 95, 12653–12656 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Brown, E. J. & Baltimore, D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397–402 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Liu, Q. et al. Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes Dev. 14, 1448–1459 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Takai, H. et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 21, 5195–5205 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health, the A–T Children's Project, the Alzheimer's Association and the Coins for Alzheimer's Research Trust.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Karl Herrup.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

ataxia telangiectasia

Parkinson's disease

Glossary

Neuronal birthday

The day on which a neuron exits mitosis and differentiates rather than re-enter a new cell cycle. Defined operationally as the last day that the adult neuron can be labelled by exogenously applied 5-bromo-2′-deoxyuridine.

Cytokinesis

The process of physically dividing the nuclear and cytoplasmic components of a cell in M phase into two daughter cells.

Phosphohistone H3

A phosphorylated form of the DNA coating protein, histone H3. Empirically, the presence of this modification is unique to M phase.

Proliferating cell nuclear antigen

(PCNA). A subunit of the DNA replication complex. Three PCNA proteins assemble as a homo-trimer encircling the double helix just ahead of the replication fork.

Ligase IV

A form of DNA ligase that rejoins 5′ and 3′ ends of apposed double-strands of DNA. This ligase isoform is specific for DNA repair, especially non-homologous end joining.

Transformed

A cellular state marked by escape from growth control mechanisms that normally regulate the cell cycle. Typically, transformed cells will form tumours in soft agar and in animals.

PC12 cells

A rat pheochromocytoma cell line. When treated with nerve growth factor, PC12 cells cease mitosis and differentiate into cells that resemble sympathetic neurons, complete with processes and functional synapses.

Mitogen

A substance, usually a protein, that induces cell division in a receptive cell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herrup, K., Yang, Y. Cell cycle regulation in the postmitotic neuron: oxymoron or new biology?. Nat Rev Neurosci 8, 368–378 (2007). https://doi.org/10.1038/nrn2124

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2124

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing