Academic journal article Genetics

Proteasomal Regulation of the Proliferation vs. Meiotic Entry Decision in the Caenorhabditis Elegans Germ Line

Academic journal article Genetics

Proteasomal Regulation of the Proliferation vs. Meiotic Entry Decision in the Caenorhabditis Elegans Germ Line

Article excerpt

ABSTRACT

Reproductive fitness in many animals relies upon a tight balance between the number of cells that proliferate in the germ line and the number of cells that enter meiosis and differentiate as gametes. In the Caenorhabditis elegans germ line, the GLP-1/Notch signaling pathway controls this balance between proliferation and meiotic entry. Here we describe the identification of the proteasome as an additional regulator of this balance. We show that a decrease in proteasome activity, through either genetic mutation or RNAi to core components of the proteasome, shifts this balance toward excess germ-line proliferation. We further demonstrate that there are likely two or more proteasome targets that contribute to excess germ-line proliferation when proteasome activity is reduced. One of these targets is likely a component or regulator of the Notch-signaling pathway, while the other functions on one of the two major redundant genetic pathways downstream of GLP-1/Notch signaling. We propose a model in which the proteasome degrades proteins that are necessary for proliferation as cells switch from proliferation to meiotic entry.

THE production of gametes is an essential process in any sexually reproducing species. In most of these species, proliferation of germ-line stem cells is needed first to generate the germ-line tissue and then to maintain a supply from which future gametes can be formed. If germ-line stem cell proliferation does not keep pace with gamete production, the population of stem cells will be depleted, resulting in sterility. Conversely, an increase in self-renewing proliferation of the germ-line stem cells at the expense of gamete production can also result in sterility, as well as tumor formation. With the large numbers of gametes that are formed over the life of some animals, it is imperative that the balance between proliferation and differentiation be fine-tuned; a slight shift in this balance will be amplified over time and greatly reduce the reproductive fitness of the animal.Much of our understanding of how the balance between germ-line proliferation and differentiation is controlled comes from study of classic genetic model organisms such as Drosophila and Caenorhabditis elegans. In both Drosophila males and females, the balance between proliferation and differentiation is a result of asymmetric division of the germline stem cells (Xie and Spradling 2000; Tulina and Matunis 2001). One daughter cell maintains contact with signaling somatic cells, resulting in retention of the stem cell property of the parent cell, while the other daughter cell is not in contact with the signaling somatic cells and begins the path to meiotic entry and differentiation (Xie and Spradling 2000; Tulina and Matunis 2001). In both male and hermaphrodite C. elegans, self-renewing proliferation of the germ-line stem cells is promoted by their proximity to a somatic signaling cell, the distal tip cell (DTC) (Kimble and White 1981). The major molecular signal promoting proliferation is transmitted through the conserved Notch-signaling pathway (Hansen and Schedl 2006; Kimble and Crittenden 2007). As part of this pathway, the membrane-bound LAG-2 ligand, which is expressed in the DTC, comes in contact with nearby proliferative cells that express the GLP-1/Notch receptor (Austin and Kimble 1987, 1989; Yochem and Greenwald 1989; Henderson et al. 1994; Taxet al. 1994). The interaction between ligand and receptor activates GLP-1/Notch signaling, which presumably culminates in the expression of genes necessary for proliferation and the inhibition of genes involved in meiotic entry. As germ cells move proximally, away from the influence of the DTC, the level of GLP-1/Notch signaling is thought to diminish, presumably allowing for the gene activity profile to switch, resulting in cells entering into meiotic prophase and eventually forming fully differentiated gametes. Numerous genetic screens for mutants that disrupt the balance between proliferation and differentiation in the C. …

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