Temporal Gradients Controlling Embryonic Cell Cycle

SIMPLE SUMMARY: Embryonic cells sense temporal gradients of regulatory signals to determine whether and when to proceed or remodel the cell cycle. Such a control mechanism is allowed to accurately link the cell cycle with the developmental program, including cell differentiation, morphogenesis, and gene expression. The mid-blastula transition has been a paradigm for timing in early embryogenesis in frog, fish, and fly, among others. It has been argued for decades now if the events associated with the mid-blastula transition, i.e., the onset of zygotic gene expression, remodeling of the cell cycle, and morphological changes, are determined by a control mechanism or by absolute time. Recent studies indicate that multiple independent signals and mechanisms contribute to the timing of these different processes. Here, we focus on the mechanisms for cell cycle remodeling, specifically in Drosophila, which relies on gradual changes of the signal over time. We discuss pathways for checkpoint activation, decay of Cdc25 protein levels, as well as depletion of deoxyribonucleotide metabolites and histone proteins. The gradual changes of these signals are linked to Cdk1 activity by readout mechanisms involving thresholds. ABSTRACT: Cell proliferation in early embryos by rapid cell cycles and its abrupt pause after a stereotypic number of divisions present an attractive system to study the timing mechanism in general and its coordination with developmental progression. In animals with large eggs, such as Xenopus, zebrafish, or Drosophila, 11–13 very fast and synchronous cycles are followed by a pause or slowdown of the cell cycle. The stage when the cell cycle is remodeled falls together with changes in cell behavior and activation of the zygotic genome and is often referred to as mid-blastula transition. The number of fast embryonic cell cycles represents a clear and binary readout of timing. Several factors controlling the cell cycle undergo dynamics and gradual changes in activity or concentration and thus may serve as temporal gradients. Recent studies have revealed that the gradual loss of Cdc25 protein, gradual depletion of free deoxyribonucleotide metabolites, or gradual depletion of free histone proteins impinge on Cdk1 activity in a threshold-like manner. In this review, we will highlight with a focus on Drosophila studies our current understanding and recent findings on the generation and readout of these temporal gradients, as well as their position within the regulatory network of the embryonic cell cycle.