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Review
. 2015;14(5):712-20.
doi: 10.1080/15384101.2015.1004937.

Neuronal cell cycle: the neuron itself and its circumstances

José M Frade  1 , María C Ovejero-Benito
Affiliations
Review

Neuronal cell cycle: the neuron itself and its circumstances

José M Frade et al. Cell Cycle. 2015.

Abstract

Neurons are usually regarded as postmitotic cells that undergo apoptosis in response to cell cycle reactivation. Nevertheless, recent evidence indicates the existence of a defined developmental program that induces DNA replication in specific populations of neurons, which remain in a tetraploid state for the rest of their adult life. Similarly, de novo neuronal tetraploidization has also been described in the adult brain as an early hallmark of neurodegeneration. The aim of this review is to integrate these recent developments in the context of cell cycle regulation and apoptotic cell death in neurons. We conclude that a variety of mechanisms exists in neuronal cells for G1/S and G2/M checkpoint regulation. These mechanisms, which are connected with the apoptotic machinery, can be modulated by environmental signals and the neuronal phenotype itself, thus resulting in a variety of outcomes ranging from cell death at the G1/S checkpoint to full proliferation of differentiated neurons.

Keywords: AD, Alzheimer disease; BDNF, brain-derived neurotrophic factor; BrdU, 5-bromo-2′-deoxyuridine; CKI, Cdk-inhibitor; CNS, central nervous system; Cdk, cyclin-dependent kinase; Cip/Kip, cyclin inhibitor protein/kinase inhibitor protein; G0, quiescent state; G1, growth phase 1; G2, growth phase 2; Ink, inhibitor of kinase; Mcm2, minichromosome maintenance 2; PCNA, proliferating cell nuclear antigen; PD, Parkinson disease; RGCs, retinal ganglion cells; Rb, Retinoblastoma; S-phase; S-phase, synthesis phase.; apoptosis; cell cycle re-entry; mitosis; neuron; p38MAPK, p38 mitogen-activated protein kinase; p75NTR, neurotrophin receptor p75; tetraploid.

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Figures

Figure 1.
Figure 1.
A scheme showing the canonical cell cycle and its main regulatory mechanisms.
Figure 2.
Figure 2.
Scheme showing the evidence for cell cycle progression in neurons. Postmitotic neurons can reactivate the cell cycle (1) using the referred pathways. In many instances, this process is aborted at the G1/S transition and the neuron die through a number of pathways initiated by either E2F1 or Myb proteins (2). There are also examples of neurons that replicate their nuclear DNA and become tetraploid (3). These neurons die if they try to undergo mitosis, and evidence exists indicating that Cdk1 is involved in this process (4). In some instances, these neurons can divide and proliferate (5). References supporting the different steps are shown in brackets.
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