Cell division requires careful stage management, much of which remains poorly understood. But several pages from the cellular prompt book have recently come to light, thanks to researchers in Britain and Canada. These researchers, who included the University of London’s Buzz Baum and the University of Montreal’s Gilles Hickson, effectively peeked backstage to observe how molecular props are reoriented during cell division, particularly the scene changes of mid anaphase, before the curtain closing known as furrow ingression begins.
Furrow ingression has been known to be cued by the recruitment of an actomyosin regulator, Ect2, to overlapping microtubules at the center of the elongating anaphase spindle. This signaling pathway, report the British and Canadian researchers, appears to be preceded by a second, parallel signaling pathway, one that triggers the relaxation of the polar cell cortex.
This new finding was described July 13 in Nature, in an article entitled, “Kinetochore-localized PP1–Sds22 couples chromosome segregation to polar relaxation.” The article emphasizes that during cell division, chromosomes are not passive, like bits of scenery pulled across the stage. They are, rather, active players. Specifically, they emit signals that influence the cortex of the cell to reinforce microtubule action, helping to instigate cytokinesis.
“[The softening of the polar cell cortex] is independent of furrow formation, centrosomes and microtubules and, instead, depends on PP1 phosphatase and its regulatory subunit Sds22,” wrote the authors of the Nature paper. “As separating chromosomes move towards the polar cortex at mid anaphase, kinetochore-localized PP1–Sds22 helps to break cortical symmetry by inducing the dephosphorylation and inactivation of ezrin/radixin/moesin proteins at cell poles.”
The new signaling pathway was first found to act in Drosophila; then it was observed in human cells. “Such evolutionary conservation from flies to humans is expected for processes as fundamental as cell division,” explained Dr. Hickson. “When chromosomes are segregated, they approach the membrane at the poles of the cell, and thanks to this enzyme's actions, this contributes to the softening of the polar membrane, facilitating the elongation of the cell and the ensuing division that occurs at the equator.”
The authors concluded that the conserved kinetochore-based phosphatase signal and substrate combination that they discovered functions “to link anaphase chromosome movements to cortical polarization, thereby coupling chromosome segregation to cell division.”
The discovery of this mechanism is a significant breakthrough in advancing knowledge about the cell division process. “We have been watching cells divide for more than 100 years, but we continue to seek to understand the molecular mechanisms involved. This is important because cell division is so central to life, and to certain diseases,” noted Dr. Hickson.
In fact, all cancers are characterized by unchecked cell division, and the underpinning processes are potential targets for therapeutic interventions that prevent cancer onset and spread. “But before we get there, we must continue to expand our knowledge about the basic processes and signals involved in normal cell division to understand how they can go awry, or how they can be exploited.”
These thoughts reinforce those expressed on a website maintained by Dr. Baum’s research group. As the website makes clear, Dr. Baum’s group studies how the dynamic shape of an animal cell is determined by the interplay of intra- and extracellular forces: “In the lab we explore the molecular, cellular, and physical processes involved using interdisciplinary approaches including molecular biology, genetics, high-content RNA interference (RNAi) screening, live cell imaging, automated image analysis, microfabrication, biophysical techniques, and computational modeling. The aim of our research is to better understand how these processes contribute to normal tissue development and homeostasis and, when they go awry, to the evolution of metastatic cancer.”