Regulation of germline proliferation and differentiation

描述(由申请人提供)：后生动物发育中的一个中心问题是细胞如何在组织特定的模式中生长或分化。我们建议在线虫的种系中分析这一基本问题的遗传和分子基础。线虫生殖系因其强大的遗传学、完整的基因组序列和细胞的简单性而特别适合于这些研究。单个体细胞调节细胞是生殖系干细胞的“小生境”，这种细胞通过保守的GLP-1/Notch信号通路促进生殖系的增殖。此外，有丝分裂/减数分裂的决定至少部分地由四个保守类别的RNA结合蛋白(Puf，Nanos，STAR/Quking，Bic-C)和新发现的细胞质Poly(A)聚合酶控制。 在接下来的五年里，我们建议分析生殖系控制的中心参与者(GLP-1信号/RNA调节因子)能够协调生殖系的生长和有丝分裂/减数分裂决定的规范的机制。首先，我们将确定由GLP-1信号直接控制的促进生殖系有丝分裂的基因。这项工作预计会将GLP-1信号与RNA调控网络联系起来，或许还会与驱动有丝分裂的细胞周期机制联系起来。其次，将分析RNA调节因子与GLP-1信号的关系、它们彼此之间的关系以及它们的目标mRNAs。这项工作预计将描绘控制生殖系生长和切换到减数分裂细胞周期的遗传电路的主干。第三，将确定和调查更多的调节者，以了解它们与已知核心参与者的遗传和分子关系。为此，我们建议将生物信息学、RNAi和传统遗传学结合起来。第四，将调查生殖系有丝分裂区域内生殖系干细胞的性质。最后，控制生殖系生长和分化的分子回路将与有丝分裂生殖系中的细胞行为联系在一起，包括细胞周期进程和组织形状。 拟议的研究将成为包括人类在内的高等生物体发育控制的范例。这项工作与健康有关有两个方面。首先，生殖系是生育的关键。其次，生殖系干细胞可能是用于疾病或受伤个体组织替代的干细胞的最终来源。

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.