Mechanisms of Asymmetric RNA segregation in C. elegans Development

描述（由申请人提供）： 该项目的三个目标是解决在动物发育早期发生的分子不对称性的功能，以及它们产生的机制。不对称的细胞分裂对于分化和发育期间细胞类型多样性的产生是必不可少的。不能正确地进行不对称细胞分裂会导致干细胞更新、组织再生的缺陷，并可能导致致癌。我们建议使用一个接近理想的自然系统，早期的C。elegans胚胎，用现代基因组工具和分析来表征特定卵裂球中细胞内容物不对称分布的机制，然后进行功能测试。具体而言，该提案旨在（1）使用卵裂球特异性分离、RNA-seq和其他高通量测序应用程序来全面绘制早期C中7个不变细胞分裂的RNA遗传和转录活性。elegans发育，（2）测试发育中不对称RNA分离的生物学意义，（3）定义不对称RNA分离所需的顺式和反式作用机制。为了实现这些目标，我们还将应用新的方法和技术来研究细胞成分的不对称分离。我们的研究计划可能会确定细胞命运的决定因素和机制，可推广到其他系统，包括人类。

DESCRIPTION (provided by applicant): The three aims of this project address the function of molecular asymmetries that occur very early in animal development, and the mechanisms by which they arise. Asymmetric cell division is essential for generation of cell-type diversity during differentiation and development. Failure o properly undergo asymmetric cell divisions can lead to defects in stem-cell renewal, tissue regeneration, and can contribute to carcinogenesis. We propose to use a near-ideal natural system, the early C. elegans embryo, to characterize the mechanisms of asymmetric distribution of cellular contents in specific blastomeres with modern genomic tools and analysis, followed by tests of function. Specifically, this proposal aims (1) to use blastomere-specific isolation, RNA- seq, and other high-throughput sequencing applications to comprehensively map RNA inheritance and transcriptional activity of seven invariant cell divisions in early C. elegans development, (2) to test the biological significance of asymmetric RNA segregation in development, and (3) to define the cis and trans-acting mechanisms required for asymmetric RNA segregation. To achieve these goals, we will also apply new approaches and technologies to the study of asymmetric segregation of cellular components. Our research plan is likely to identify cell-fate determinants and mechanisms that are generalizable to other systems, including humans.