Grant: Discovery Grants Program - Individual

I study the basic mechanisms that control chromosome movements during cell division. Prior to cell division, each chromosome is duplicated; I study how each of the two daughter cells receives one copy of each chromosome. This is important because chromosomes carry genetic information and errors in the distribution of genetic material can cause cell death, birth defects and cancers. Some of our work deals with the forces that move the chromosomes to the two new cells. In cells with pairs of duplicated chromosomes, proper chromosome distribution arises because partner chromosomes line up in the middle of the cell and spindle fibres connect partners to opposite poles. The partners separate simultaneously and move to opposite poles; each spindle fibre shortens as its chromosome moves. This is analogous to pairs of differently coloured boats lined up in the middle of a lake. The 2 boats of each colour are connected by cables to docks on opposite sides of the lake so each dock gets one boat of each colour. Most cell biologists think that boats (chromosomes) are reeled to their docks (poles) by the action of winches at the dock, or winches at the boat, or both. My experiments dispute this idea: we severed the cable (the spindle fibre) with laser or ultraviolet light microbeam irradiations and the boats still moved to their dock. We suggest that the force for movement arises from water currents (from a spindle matrix) and that the cable does not pull the boat but rather guides the boat to the dock. Because the cables (spindle microtubules) resist bending, they resist the movements of the boats, so the speed that a boat moves to its dock is governed by the speed of reeling in the cable. Our proposed experiments study how the spindle matrix produces the force, and how other proteins might be involved. For example, we will stabilise the cables so the winches don?t work (using a drug called paclitaxel) and then sever a cable. If the current produces the force to move the boats, as we believe, the boat should move toward the dock when the cable impediment is removed. Our proposed experiments aim to understand the basic mechanisms that move chromosomes. We also study a less-well understood issue, communication between the boats. Each boat moves to its dock after a starter?s whistle is sounded (a global start signal), and it often is assumed that that is all that is needed. But we have identified various local signals between boats that can alter their motion to their dock. For example, after weaker microbeam irradiation damages the cable between a green boat and its dock, both that boat and its partner green boat (going to the other dock) stop moving: partner boats communicate. In this particular example we have some idea of the mechanism. Boats of the same colour when moving to opposite poles are connected by bungee cords (in cells they are called ?tethers?), identified by cutting the trailing part of the boat (a trailing arm of the chromosome). The boats keep moving as the severed part of the boat is pulled to the partner boat by the contracting bungee cord. We propose to cut a bungee cord of a boat (with a laser) and then damage the associated cable: if the partners communicate via the bungee cord, communication should stop when we cut a bungee cord so the boat with damaged cable will stop moving but its partner will not. In the other examples of ?communication? we do not understand how the coordinated movements arise. Our experiments aim to better understand these communication systems. By understanding them we can better understand how errors arise and how one might ameliorate them.