Regulation of germline proliferation and differentiation

描述（由申请人提供）：后生动物发育的一个中心问题是细胞如何以组织特异性模式生长或分化。我们建议分析秀丽隐杆线虫生殖系中这一基本问题的遗传和分子基础。秀丽隐杆线虫生殖系特别适合这些研究，因为它具有强大的遗传学，完整的基因组序列和细胞简单性。单个体细胞调节细胞作为生殖系干细胞的“生态位”，通过保守的GLP-1/Notch信号通路促进生殖系增殖。此外，有丝分裂/减数分裂的决定至少部分是由四个保守类（Puf, Nanos, STAR/quaking, Bic-C）的rna结合蛋白以及新发现的细胞质聚(a)聚合酶控制的。

DESCRIPTION (provided by applicant): A central problem in metazoan development is how cells are governed to grow or differentiate in a tissue-specific pattern. We propose to analyze the genetic and molecular basis of this fundamental problem in the germ line of the nematode Caenorhabditis elegans. The C. elegans germ line is particularly suitable for these studies because of its powerful genetics, completed genome sequence, and cellular simplicity. A single somatic regulatory cell serves as a "niche" for germline stem cells, and this cell promotes germline proliferation by the conserved GLP-1/Notch signaling pathway. Moreover, the mitosis/meiosis decision is controlled, at least in part, by RNA-binding proteins of four conserved classes (Puf, Nanos, STAR/quaking, Bic-C) plus a newly discovered cytoplasmic poly(A) polymerase. In the next five years, we propose to analyze mechanisms by which central players of germline control (GLP-1 signaling/RNA regulators) are able to orchestrate growth of the germ line and specification of the mitosis/meiosis decision. First, we will identify genes directly controlled by GLP-1 signaling to promote germline mitoses. This work is predicted to link GLP-1 signaling with the RNA regulatory network and perhaps with the cell cycle machinery driving mitosis. Second, RNA regulators will be analyzed with respect to their relationship to GLP-1 signaling, their relationships among each other and their target mRNAs. This work is predicted to delineate the backbone of the genetic circuit controlling germline growth and the switch into the meiotic cell cycle. Third, additional regulators will be identified and investigated to learn their genetic and molecular relationships with the known central players. To this end, we propose to combine bioinformatics, RNAi and traditional genetics. Fourth, the nature of germline stem cells within the germline mitotic region will be investigated. Finally, the molecular circuit controlling germline growth and differentiation will be linked to cellular behaviors in the mitotic germ line, including cell cycle progression and tissue shape. The proposed studies will serve as a paradigm for developmental controls in higher organisms, including humans. The health-relatedness of this work is two-fold. First, the germ line holds the key to fertility. Second, germline stem cells may be the ultimate source of stem cells for tissue replacement in diseased or injured individuals.