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.
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
Open Access articles citing this article.
Cell Death Discovery Open Access 24 November 2022
Aβ-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation
Experimental & Molecular Medicine Open Access 02 September 2022
Cell and Tissue Research Open Access 29 January 2022
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
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).
Cai, L., Hayes, N. L. & Nowakowski, R. S. Local homogeneity of cell cycle length in developing mouse cortex. J. Neurosci. 17, 2079–2087 (1997).
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).
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).
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).
Miale, I. L. & Sidman, R. L. An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp. Neurol. 4, 277–296 (1961).
Uzman, L. L. The histogenesis of the mouse cerebellum as studied by its tritiated thymidine uptake. J. Comp. Neurol. 114, 137–159 (1960).
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).
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).
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).
Taupin, P. Neurogenesis in the adult central nervous system. C. R. Biol. 329, 465–475 (2006).
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).
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).
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).
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).
Ruiz i Altaba, A., Palma, V. & Dahmane, N. Hedgehog–Gli signalling and the growth of the brain. Nature Rev. Neurosci. 3, 24–33 (2002).
Clarke, A. R. et al. Requirement for a functional Rb-1 gene in murine development. Nature 359, 328–330 (1992).
Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).
Lee, E. Y. et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359, 288–294 (1992).
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.
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).
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.
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).
Blackshaw, S. et al. Genomic analysis of mouse retinal development. PLoS Biol. 2, E247 (2004).
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).
Lukaszewicz, A. et al. G1 phase regulation, area-specific cell cycle control, and cytoarchitectonics in the primate cortex. Neuron 47, 353–364 (2005).
Gao, Y. et al. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95, 891–902 (1998).
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).
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).
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).
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).
Chun, J. Cell death, DNA breaks and possible rearrangements: an alternative view. Trends Neurosci. 23, 407–409 (2000).
Gilmore, E. C., Herrup, K., Nowakowski, R. S. & Caviness, V. S. Jr. Reply. Trends Neurosci. 23, 408–409 (2000).
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).
Baker, S. J. & McKinnon, P. J. Tumour-suppressor function in the nervous system. Nature Rev. Cancer 4, 184–196 (2004).
O'Driscoll, M. & Jeggo, P. A. The role of double-strand break repair- insights from human genetics. Nature Rev. Genet. 7, 45–54 (2006).
Murphy, M. et al. Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nature Genet. 15, 83–86 (1997).
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).
Kozar, K. et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118, 477–491 (2004).
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).
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).
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.
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).
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).
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.
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Wu, L. et al. Extra-embryonic function of Rb is essential for embryonic development and viability. Nature 421, 942–947 (2003).
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).
Vincent, I., Rosado, M. & Davies, P. Mitotic mechanisms in Alzheimer's disease? J. Cell Biol. 132, 413–425 (1996).
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).
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).
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.
Yang, Y., Geldmacher, D. S. & Herrup, K. DNA replication precedes neuronal cell death in Alzheimer's disease. J. Neurosci. 21, 2661–2668 (2001).
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).
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).
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).
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).
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).
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).
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).
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).
Johansson, A. et al. Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 20, 367–374 (2005).
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).
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).
Ranganathan, S. & Bowser, R. Alterations in G1 to S phase cell-cycle regulators during amyotrophic lateral sclerosis. Am. J. Pathol. 162, 823–835 (2003).
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).
Yang, Y. & Herrup, K. Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J. Neurosci. 25, 2522–2529 (2005).
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).
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).
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).
West, A. B., Dawson, V. L. & Dawson, T. M. To die or grow: Parkinson's disease and cancer. Trends Neurosci. 28, 348–352 (2005).
Love, S. Neuronal expression of cell cycle-related proteins after brain ischaemia in man. Neurosci. Lett. 353, 29–32 (2003).
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).
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).
Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).
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).
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).
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).
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).
Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).
Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527 (1995).
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).
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).
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).
Calhoun, M. E. et al. Neuron loss in APP transgenic mice. Nature 395, 755–756 (1998).
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).
Hock, B. J. Jr. & Lamb, B. T. Transgenic mouse models of Alzheimer's disease. Trends Genet. 17, S7–S12 (2001).
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).
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).
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).
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).
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).
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.
Dyer, M. A. & Cepko, C. L. p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations. J. Neurosci. 21, 4259–4271 (2001).
Dyer, M. A. & Cepko, C. L. p57Kip2 regulates progenitor cell proliferation and amacrine interneuron development in the mouse retina. Development 127, 3593–3605 (2000).
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).
Nguyen, L. et al. p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes Dev. 20, 1511–1524 (2006).
Cicero, S. & Herrup, K. Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J. Neurosci. 25, 9658–9668 (2005).
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).
Fu, A. K. et al. Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nature Neurosci. 4, 374–381 (2001).
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).
Fu, W. Y. et al. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nature Neurosci. 10, 67–76 (2007).
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).
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).
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).
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.
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).
Buss, R. R. & Oppenheim, R. W. Role of programmed cell death in normal neuronal development and function. Anat. Sci. Int. 79, 191–197 (2004).
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.
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).
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).
Field, S. J. et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549–561 (1996).
Yamasaki, L. et al. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85, 537–548 (1996).
McKinnon, P. J. ATM and ataxia telangiectasia. EMBO Rep. 5, 772–776 (2004).
Shiloh, Y. & Kastan, M. B. ATM: genome stability, neuronal development, and cancer cross paths. Adv. Cancer Res. 83, 209–254 (2001).
Kastan, M. B. & Lim, D. S. The many substrates and functions of ATM. Nature Rev. Mol. Cell Biol. 1, 179–186 (2000).
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).
Ohshima, T. et al. Migration defects of cdk5−/− neurons in the developing cerebellum is cell autonomous. J. Neurosci. 19, 6017–6026 (1999).
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).
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).
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).
Sicinski, P. et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82, 621–630 (1995).
Sicinski, P. et al. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384, 470–474 (1996).
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).
Georgia, S. & Bhushan, A. β cell replication is the primary mechanism for maintaining postnatal β cell mass. J. Clin. Invest. 114, 963–968 (2004).
Ciemerych, M. A. et al. Development of mice expressing a single D-type cyclin. Genes Dev. 16, 3277–3289 (2002).
Lee, M. H. et al. Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev. 10, 1621–1632 (1996).
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).
Brown, E. J. & Baltimore, D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397–402 (2000).
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).
Takai, H. et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 21, 5195–5205 (2002).
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.
The authors declare no competing financial interests.
- 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.
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.
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.
A substance, usually a protein, that induces cell division in a receptive cell.
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
This article is cited by
Nature Reviews Neurology (2023)
Cell and Tissue Research (2023)
Cell Death Discovery (2022)
Aβ-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation
Experimental & Molecular Medicine (2022)
Prediction of differentially expressed microRNAs in blood as potential biomarkers for Alzheimer’s disease by meta-analysis and adaptive boosting ensemble learning
Alzheimer's Research & Therapy (2021)