Proteasomal regulation of proliferation in the C. elegans germ line

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The reproductive fitness of many animals relies upon the production of large numbers of gametes over an extended period of time. The number of gametes produced over the life of the animal often far exceeds the number of cells that exist in the gonad at any given time. This is possible due to the existence of germline stem cells, which divide to give rise to two types of daughter cells. One daughter cell becomes the gamete (differentiation), while the other daughter cell retains the same characteristics as the parent (self-renewal), which can then give rise to both types of daughter cells. Therefore, a population of cells is always maintained from which future gametes can be generated. A tight balance must be maintained between the number of daughter cells that become gametes and the number of daughter cells that self-renew because a shift towards either fate will eventually result in sterility. The molecular mechanisms involved in maintaining this balance are not well understood in any system. We are using the germ line of the model organism, C. elegans, as a model to understand how the balance between stem cell differentiation and self-renewal is maintained. We have previously found that the proteasome, which degrades proteins in the cell, is needed for this balance to be maintained properly. We have performed genetic analysis that has helped in our understanding of the possible mechanisms by which the proteasome functions to help control this balance. We found that at least part of this mechanism is to control the Notch signaling pathway; this signaling pathway is highly utilized in virtually all multicellular animals during development. We have identified a potentially novel mechanism by which the proteasome controls Notch signaling. Our current proposal aims to identify the specific proteins that are targeted by the proteasome and understand how their degradation is necessary for the balance between differentiation and self-renewal to be maintained in the C. elegans germ line, which will help in our general understanding of how this balance is maintained in all stem cell systems. Additionally, it will also help in our understanding of the regulation of the highly conserved Notch signaling pathway.