Cell cycle re-entry in neurons and apoptosis

Unlike most cell types, neurons are believed to have permanently blocked their capacity to proliferate once they are differentiated, being typically found in a quiescent state in the adult nervous system. 

However, a number of genes that encode for regulators of G1/S transition, including cyclin D1, Cdk4, Rb proteins, E2Fs, and CKIs, can be detected in different structures of the normal adult brain. 

Most of these transcripts are actually translated, as evidenced by the detection of the proteins they encode in normal adult neurons.  

Traditionally, the presence of core cell cycle regulators in adult neurons has been explained as these molecules may fulfill differentiative functions, including neuronal migration, neuronal maturation, and synaptic plasticity. 

Nevertheless, it remains plausible that, potentially, these proteins could also lead to cell cycle re-entry provided that specific conditions are met. 

In this regard, there are examples in which specific neuronal types, including sympathetic and cortical neurons, upregulate the expression of cell cycle markers and try to reactivate the cell cycle when subjected to acute insults such as neurotrophic factor deprivation, activity withdrawal, DNA damage, oxidative stress, and excitotoxicity. 

Under these conditions, they usually die at the G1/S checkpoint before any sign of DNA synthesis can be observed (for a review see refs. 43,44). This process, classically referred to as “abortive cell cycle re-entry,” is characterized by upregulation of cyclin D-Cdk4/6 activity and deregulation of E2F transcription factors, followed by cell death. 

In this regard, E2F1 can be a trigger of neuronal apoptosis, and 2 proapoptotic signaling pathways have been shown to be activated by this transcription factor in cerebellar granule cells and cortical neurons. 

These pathways include the activation of Bax/caspase-3 in a p53-independent manner and the induction of the Cdk1/FOXO1/Bad pathway.  

In addition, deregulation of p130/E2F4, a repressive complex that maintains the postmitotic state of neurons, has also been shown to participate in the induction of neuronal apoptosis through the upregulation of B-myb and C-myb.  

Overall, these observations indicate that a number of signaling pathways triggered by different environmental conditions can elicit cell cycle reactivation and cell death in specific neuronal phenotypes.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418291/