The O'Farrell lab at UCSF

Cell Cycle Research

Anaphase Chromosomes
Syncytial embryo in anaphase
We are fascinated with the control of timing during development. Major advances have outlined the mechanisms of spatial patterning of the embryo, but little is known about the orchestration of events in time. The earliest stages of development isolate temporal control and the key target of the temporal control is the cell cycle.

Early embryogenesis is characterized by several exceedingly rapid cell cycles, which are thought to set the stage for the patterning events that will follow. This phenomenon is conserved to all metazoan phyla. As gastrulation approaches, there is a remodeling of fundamental cell behaviors collectively referred to as the mid-blastula transition (MBT): the cycles slow and eventually arrest, cells undergo cellularization and gross rearrangement, and there is a major turnover of the mRNA population as the embryo goes through the maternal-zygotic transition (MZT).

late replication
Interphase progressively lengthens over cycles 11-14 as origins of replication no longer fire simultaneously. Satellite 356 is among the late replicating sequences (DNA in blue; satellite 356 in pink)
Taken by Tony Shermoen
Cell cycle slowing is the centerpiece of the MBT. Our lab explores the timing of the extremely rapid early embryonic cycles, and the abrupt slowing of the cycle precisely after the 13th mitosis. We hope to define the molecular basis of the switch and the mechanisms that so precisely time the transition.

We have shown that S phase duration is the major timer of the early embryonic cycle (McCleland et al., 2009), that S phase length increases because of delays in the replication of heterochromatic satellite sequences (Shermoen et al., 2011), that high “mitotic” cyclin:Cdk1 drives early replication of satellite sequences during the fast early cycles, and that the abrupt slowing of cell cycle 14 begins with a much longer S phase (~60 min) that requires the downregulation of Cdc25 and secondarily cyclin:Cdk1 (Farrell et al, 2012).

String experssion in the Early Embryo
From the seminal paper: cdc25stg expression (pink) just prior to gastrulation (see Edgar, 1989)
The questions we are currently investigating include:
  1. What triggers abrupt downregulation of Cdc25 and cyclin:Cdk1 at the MBT?
  2. What is the mechanism that governs the timing of replication within S phase 14 so that heterochromatic sequences replicate late?
  3. What times the progress of early extremely rapid cell cycles?
  4. What governs the onset of zygotic gene expression at the end of cycle 13?

      · Cell Cycle     · Mitochondria