Cytoplasmic dynein and KASH5: partners in fertility

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The birth of a healthy baby is the culmination of many complex processes, the first of which is the production of normal egg and sperm. This needs a specialised type of cell division, called meiosis. In most cells in our body, we have two copies of each chromosome: one each from our mother and father. Early during the first meiotic cell division, the two copies pair up in a process called synapsis, and swap regions of their DNA to give new combinations of genes. Synapsis is made much more efficient by movement of the chromosomes after they become attached to the membrane that surrounds the chromosomes, the nuclear envelope (NE). Chromosome movement is driven by a tiny motor, dynein, that walks along protein tracks in the cell pulling cargo with it. Dynein is linked to the chromosomes in meiosis by a protein complex that spans the NE, which contains a protein called KASH5. Dynein at the NE is also needed right after fertilization, when it transports the nucleus of the egg towards the sperm nucleus to allow their DNA to mix before the first division of the embryo. It is not known yet how dynein binds to the NE in this situation, but we predict that KASH5 does this job too. In this project, we will analyse in depth the mechanism and regulation of the dynein-KASH5 interaction, and see if it is also needed for pronuclear migration. Dynein is a very complex protein that is made up of 6 different subunits. Our preliminary work strongly suggests that KASH5 binds to dynein's light intermediate chains (LICs). We will work out which parts of KASH5 bind to which bit of the LIC, and how this interaction is regulated during the cell cycle. Very recent work has shown that dynein is activated by forming a stable complex with two other protein components: dynactin, and one of several adaptor proteins. We think that KASH5 acts as an adaptor protein too. We also predict that the LICs play a crucial role in assembling these active dynein complexes. We will test those ideas here.