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.
Our first aim i s to determine whether the cell cycle acts as a clock for the MBT or whether cell cycle and MBT are controlled by independent but synchronized clocks. At present, data suggests two different clocks but with a safety mechanism whereby continued cell cycles defer the MBT. We will manipulate cell cycle regulators to alter the cycle, and examine the effect on timing of MBT events.
Our second aim i s to investigate regulation of cell cycle duration. We recently found that the time required to replicate the genome dictates the duration of the early cycles. We will investigate the molecular mechanisms governing S phase length and determine the importance of S phase elongation in execution of the MBT. Finally, transition from the rapid cell cycle of the early embryo to the prolonged cycle of the post MBT embryo depends on the abrupt elimination of maternal Cdc25 at the beginning of cycle 14.
Our third aim i s to determine how the embryo down-regulates Cdc25 mRNA and protein to trigger the major changes at the MBT. For this we have a new antibody to follow the behavior of Cdc25 protein and we will identify the mechanisms involved in destabilizing the mRNA. These studies will probe the fundamental question of how time is measured in biological systems, yielding advances to understanding of development and cancer.

Public Health Relevance

When an egg develops into an organism, the number of cells goes from one to many millions. We are probing how cells keep track of time so that they know when they should divide and when they should arrest the cell cycle, the factors that distinguish the creative growth in embryogenesis from the destructive growth of a tumor. The faithful regulation of proliferation we are studying is essential if organisms are to avoid birth defects and cancer, two issues of major importance in human health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Development - 2 Study Section (DEV2)
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Hamlet, Michelle R
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Duronio, Robert J; O'Farrell, Patrick H; Sluder, Greenfield et al. (2017) Sophisticated lessons from simple organisms: appreciating the value of curiosity-driven research. Dis Model Mech 10:1381-1389
Yuan, Kai; O'Farrell, Patrick H (2016) TALE-light imaging reveals maternally guided, H3K9me2/3-independent emergence of functional heterochromatin in Drosophila embryos. Genes Dev 30:579-93
Yuan, Kai; Seller, Charles A; Shermoen, Antony W et al. (2016) Timing the Drosophila Mid-Blastula Transition: A Cell Cycle-Centered View. Trends Genet 32:496-507
Yuan, Kai; O'Farrell, Patrick H (2015) Cyclin B3 is a mitotic cyclin that promotes the metaphase-anaphase transition. Curr Biol 25:811-816
O'Farrell, Patrick H (2015) Growing an Embryo from a Single Cell: A Hurdle in Animal Life. Cold Spring Harb Perspect Biol 7:
Farrell, Jeffrey A; O'Farrell, Patrick H (2014) From egg to gastrula: how the cell cycle is remodeled during the Drosophila mid-blastula transition. Annu Rev Genet 48:269-94
Yuan, Kai; Shermoen, Antony W; O'Farrell, Patrick H (2014) Illuminating DNA replication during Drosophila development using TALE-lights. Curr Biol 24:R144-5
Farrell, Jeffrey A; O'Farrell, Patrick H (2013) Mechanism and regulation of Cdc25/Twine protein destruction in embryonic cell-cycle remodeling. Curr Biol 23:118-26
Yuan, Kai; Farrell, Jeffrey A; O'Farrell, Patrick H (2012) Different cyclin types collaborate to reverse the S-phase checkpoint and permit prompt mitosis. J Cell Biol 198:973-80
Farrell, Jeffrey A; Shermoen, Antony W; Yuan, Kai et al. (2012) Embryonic onset of late replication requires Cdc25 down-regulation. Genes Dev 26:714-25

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