Proteasomal regulation of proliferation in the C. elegans germ line

许多动物的生殖健康依赖于在很长一段时间内产生大量配子。在动物的一生中产生的配子数量往往远远超过在任何给定时间存在于性腺中的细胞数量。这是由于生殖系干细胞的存在，这种干细胞分裂后会产生两种子细胞。一个子细胞成为配子（分化），而另一个子细胞保持与亲本相同的特征（自我更新），然后可以产生两种类型的子细胞。因此，总能维持一个细胞群，从而产生未来的配子。在成为配子的子细胞数量和自我更新的子细胞数量之间必须保持严格的平衡，因为向任何一种命运的转变最终都会导致不育。维持这种平衡的分子机制在任何系统中都没有得到很好的理解。我们正在使用模式生物秀丽隐杆线虫的种系作为模型，以了解干细胞分化和自我更新之间的平衡是如何维持的。我们之前已经发现，蛋白酶体，降解细胞中的蛋白质，是维持这种平衡所必需的。我们已经进行了遗传分析，这有助于我们理解蛋白酶体帮助控制这种平衡的可能机制。我们发现这种机制至少部分是控制Notch信号通路；这种信号通路在几乎所有多细胞动物的发育过程中都被高度利用。我们已经确定了蛋白酶体控制Notch信号传导的潜在新机制。我们目前的建议旨在确定蛋白酶体靶向的特定蛋白质，并了解它们的降解是如何在秀丽隐杆线虫生殖系中维持分化和自我更新之间的平衡所必需的，这将有助于我们对所有干细胞系统中如何维持这种平衡的一般理解。此外，它也将有助于我们理解高度保守的Notch信号通路的调控。

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.