Differentiation and De-Differentiation—Neuronal Cell-Cycle Regulation During Development and Age-Related Neurodegenerative Disorders

Abstract

The eukaryotic cell cycle is an evolutionary highly conserved process that results in cell division into two daughter cells. Nondividing cells rest outside the cell cycle. The cell cycle consists of an ordered set of events that are tightly regulated by defined temporal and spatial expression, subcellular localization, and degradation of cell cycle regulators. The transition through the cell cycle is controlled by ‘stop’ and ‘go signals’ at defined checkpoints. These checkpoints allow alternate decisions between further progression through the cell cycle and growth arrest, in order to provide potentials for DNA repair or induction of apoptosis. Postmitotic neurons in the CNS are generated from neuroepithelial stem cells, which are multipotent cells that differentiate into progenitor cells of neurons and glial cells. Differentiated neurons are postmitotic cells that have permanently withdrawn from the cell cycle. Currently accumulating evidence, however, shows that differentiated neurons express a number of cell cycle regulators which suggest a role of these proteins beyond cell cycle regulation. Under conditions of neurodegeneration in Alzheimer’s disease, neurons leave their differentiated stage and re‐enter the cell cycle. This process which is driven by an abnormal activation of mitogenic pathways eventually results in cell death. Alzheimer’s disease should, thus, be added to the list of proliferative disorders such as cancer, cardiovascular disease, infections and autoimmune diseases, where cell cycle regulators are recognized targets for treatment. Here we attempt to give an overview on the current state of knowledge on the regulation of the cell cycle in neurons under physiological and pathophysiological conditions.