Neurons are highly differentiated cells that normally never enter a cell cycle; if they do, the result is usually death, not division. For example, cerebellar granule neurons in staggerer and lurcher mutant mice initiate a cell cycle-like process just before they die. E2F1 is a transcription factor that promotes cell cycle progression. Because E2F1 is also involved in apoptosis, we bred double mutants (E2f1-/-; staggerer and E2f1-/-; lurcher) to assess its role in the cell cycle-related death of cerebellar granule cells in vivo. We found neither granule cell cycle initiation nor cell death was significantly altered in either double mutant. However, after postnatal day 10, neurons throughout the CNS of E2f1-/- and E2f1+/- animals were found to express cell cycle proteins and replicate their DNA. Whereas Map2 and synapsin1 staining are little altered, there is a reduction of calbindin in Purkinje cell dendrites at 1 year of age, suggesting that the mutant cells also undergo a slow, subtle atrophy. These events are cell autonomous, because cultured E2f1-/- cortical neurons "cycle" in vitro, whereas wild-type neurons do not. Our results suggest that, in mature CNS neurons, E2F1 functions as a cell cycle suppressor.