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  • Review Article
  • Published:

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

Nature Reviews Neuroscience volume 8, pages 368–378 (2007)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, 08854, New Jersey, USA

    Karl Herrup

  2. Department of Neurosciences, Center for Translational Neuroscience, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, 44106, Ohio, USA

    Yan Yang

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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.

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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

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