Abstract
BackgroundMost differentiating cells are arrested in G1-phase of the cell cycle and this proliferative quiescence appears important to allow differentiation programmes to be executed. An example occurs in the Drosophila eye imaginal disc, where all cells are synchronized and arrested in G1 phase prior to making a fate choice either to initiate the first round of photoreceptor differentiation or to re-enter one terminal mitosis.ResultsWe have analysed the mechanism of this temporally regulated G1-phase in order to develop an integrated model of this proliferative regulation. We find that an overlapping set of cell cycle inhibitors combine to form an efficient barrier to cell cycle progression. This barrier depends on both the primary secreted signals that drive retinal development, Dpp and Hh. Each of these has distinct, as well as partially overlapping functions, in ensuring that Cyclin E and dE2F1 are kept in check. Additionally, inhibition of Cyclin A by Roughex is essential, and this regulation is independent of Dpp and Hh.ConclusionOne implication of these results is to further support the idea that Cyclin A has important functions in S-phase entry as well as in mitosis. The unexpectedly complex network of regulation may reflect the importance of cells being uniformly ready to respond to the inductive signals that coordinate retinal differentiation.
Highlights
Most differentiating cells are arrested in G1-phase of the cell cycle and this proliferative quiescence appears important to allow differentiation programmes to be executed
This is only slightly longer than the estimate of the normal G1 phase of cells in the proliferating region of the disc. This is based on the observation that the doubling time for cells in the eye disc is approximately 12 hours [18], and that the proportion of cells in G1 phase in proliferating disc cells is one third [19]. These estimates imply that the formation of this non-proliferative region (NPR) depends significantly on cell cycle synchronization as they approach the morphogenetic furrow (MF), as well as on specific arrest mechanisms
Note that in the anterior part of the NPR, cells do not enter G1 arrest until after mitosis, so the last cells to be detected by BrdU staining enter G1 one or two rows later, after completion of G2 and M-phases
Summary
Most differentiating cells are arrested in G1-phase of the cell cycle and this proliferative quiescence appears important to allow differentiation programmes to be executed. An example occurs in the Drosophila eye imaginal disc, where all cells are synchronized and arrested in G1 phase prior to making a fate choice either to initiate the first round of photoreceptor differentiation or to re-enter one terminal mitosis. A well conserved aspect of this developmental regulation is that cells normally arrest in G1-phase of the cell cycle prior to differentiation. This provides a quiescent stage for differentiation to begin and, once cells start to adopt their terminal fate, most will never re-enter a proliferative state. The Drosophila eye provides an experimentally amenable example of developmentally regulated proliferation and has been extensively studied as a model. After the MF passes, those cells that have not yet started to differentiate as photore-
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