Developmental Programs of Cell Cycle Control

University Of California, San Francisco, San Francisco CA

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Abstract

Orchestration of the dynamic events of development requires precise timing. In contrast to the much-studied spatial controls in development, we know little about temporal regulation. We are probing the intimate coordination in time between cell proliferation and embryonic development. We focus on the specialized cell cycles of the early Drosophila embryo, the characteristics of which are highly conserved across evolution. Embryogenesis begins with extremely fast, synchronous cell cycles, in the absence of gene expression. No growth accompanies these cycles, which divide the large egg cytoplasm into smaller cells. At cycle 9. the cycles begin to slow, initially very slightly but progressively, until mitosis 13 where the cell cycle abruptly lengthens. This shift in the character of the cell cycles culminates in a sudden and strong activation of transcription, and the onset of gastrulation - a transition called the Mid-Blastula Transition (MBT). All future divisions require gene expression and occur in intricate spatial patterns. We are probing the mechanisms that time and coordinate events for the faithful execution of the MBT, in particular the shift in cell cycle timing. We found that S phase prolongation paces the early cycles. In fast S phases, all sequences replicate at the same time, whereas S phase slows in conjunction with onset of distinctive behaviors of euchromatin and heterochromatin and late replication of satellite sequences. High cyclin:Cdk1 during the early cycles drives early replication of satellites and regulated protein destruction of Cdkl activator Cdc25/Twine in cycle 14 leads to downregulation of cyclin:Cdk1 and onset of the late replication program at the MBT. These advances in understanding of the system have led us to focus on the mechanisms governing timing of late replication of the satellite sequences and introduction of heterochromatin. We are also continuing to explore the events that trigger the onset of transcription at the MBT and the abrupt onset of Cdc25/Twine destruction. These studies will probe the fundamental question of how time is measured in biological systems, yielding advances to understanding of development and cancer.