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.

NRIF (neurotrophin receptor interacting factor) is a ubiquitously expressed zinc finger protein of the Krüppel family which interacts with the neurotrophin receptor p75NTR. The interaction was first detected in yeast and then biochemically confirmed using recombinant GST–NRIF fusions and p75NTR expressed by eukaryotic cells. Transgenic mice carrying a deletion in the exon encoding the p75NTR‐binding domain of NRIF display a phenotype which is strongly dependent upon genetic background. While at the F2 generation there is only limited (20%) embryonic lethality, in a congenic BL6 strain nrif−/− mice cannot survive beyond E12, but are viable and healthy to adulthood in the Sv129 background. The involvement of NRIF in p75NTR/NGF‐mediated developmental cell death was examined in the mouse embryonic neural retina. Disruption of the nrif gene leads to a reduction in cell death which is quantitatively indistinguishable from that observed in p75NTR−/− and ngf−/− mice. These results indicate that NRIF is an intracellular p75NTR‐binding protein transducing cell death signals during development.