Abstract
The mechanisms of cell cycle exit by neurons remain poorly understood. Through genetic and developmental analysis of Drosophila eye development, we found that the cyclin-dependent kinase-inhibitor Roughex maintains G1 cell cycle exit during differentiation of the R8 class of photoreceptor neurons. The roughex mutant neurons re-enter the mitotic cell cycle and progress without executing cytokinesis, unlike non-neuronal cells in the roughex mutant that perform complete cell divisions. After mitosis, the binucleated R8 neurons usually transport one daughter nucleus away from the cell body into the developing axon towards the brain in a kinesin-dependent manner resembling anterograde axonal trafficking. Similar cell cycle and photoreceptor neuron defects occurred in mutants for components of the Anaphase Promoting Complex/Cyclosome. These findings indicate a neuron-specific defect in cytokinesis and demonstrate a critical role for mitotic cyclin downregulation both to maintain cell cycle exit during neuronal differentiation and to prevent axonal defects following failed cytokinesis.
Highlights
The near universality of neuronal cell cycle exit implies robust barriers to division
We describe cell cycle re-entry in differentiating photoreceptor neurons lacking the cyclin dependent kinase inhibitor, roughex, or certain components of the Anaphase Promoting Complex/Cyclosome (APC/C), and the cellular consequences of such deregulated neuronal cell cycles in the differentiating Drosophila eye
Adult rux mutant eyes have a reduced number of ommatidia that often lack a variable number of cells(Figure 1A, 1B) [28]
Summary
The near universality of neuronal cell cycle exit implies robust barriers to division. These could include additional neuron-specific and redundant barriers to cell cycle entry and progression, and surveillance mechanisms to eliminate neurons that evade them. It is often speculated that the cell cycle might be lethal for neurons, or that inability to duplicate axons may prevent neuronal division. In the case of horizontal cells that give rise to retinoblastoma in the mouse retina, mutations at three Rb-family loci are required for transformation [2]. Such genotypes cause other types of retinal neuron to die [2]. Much remains to be learned concerning cell cycle status and mechanisms in neurons, and its relationship to disease
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