Genes controlling asymmetric cell divisions during C. elegans development

线虫发育过程中控制不对称细胞分裂的基因

• 批准号: 7197375
• 负责人: GIAN GARRIGA
• 金额: $ 25.76万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197375
• 关键词: Adopted; Apoptotic; Caenorhabditis elegans; Cell Nucleus; Cell division; Cells; Development; Event; Family suidae; Genes; Goals; Malignant Neoplasms; Mediating; Modeling; Mutation; Nervous system structure; Neurons; Pathway interactions; Process; RNA Interference; Research; Role; Signal Transduction; Specific qualifier value; Sus scrofa; Testing; cell type; daughter cell; gastrin-releasing peptide 1; human disease; interest; neuroblast; receptor; research study

DESCRIPTION (provided by applicant): A fundamental question in development is how cells are specified. Elucidating mechanisms of cell-type specification is essential to the understanding and eventually treating human diseases, such as cancer, where this process is altered. One mechanism that specifies cell type is Asymmetric Cell Division, where a cell divides to produce two daughter cells that adopt distinct fates. Both intracellular asymmetric molecules and cell signaling appear to polarize neuroblasts, but a connection between the two mechanisms has been lacking. We have found that signaling is essential for certain asymmetric divisions that produce apoptotic cells and neural precursors and have identified molecules that are asymmetrically distributed in these divisions. The overall goal of our research is to understand how both cell intrinsic mechanisms and signaling regulate the fates of the neurons that are generated during these divisions. The proposal has three aims. 1) We propose to determine how the cytohesin GRP-1 regulates asymmetric cell divisions. Our model proposes that GRP-1 functions in V5 to regulate signaling between V5 and asymmetrically dividing neuroblasts, and we will test this idea rigorously for several divisions that require GRP-1 function. We will test the model that PI3K regulates GRP-1 and mediates its effects though ARF-1 and ARF-6. GRP-1's surprising localization to the nucleus raises the interesting possibility that cytohesins may function there, and we will ask whether GRP-1 carries out its functions in the nucleus. Finally, we will pursue RNG-1 and CNT-2, two molecules that may function in the GRP-1 pathway. 2) We propose to determine how Wnts regulate asymmetric divisions of the Q neuroblast, which also require both PIG-1 and GRP-1 function. Our preliminary experiments indicate that three Wnts and two Frizzled receptors are involved in these divisions. We will test the roles of the remaining Wnts and Wnt receptors, characterize the effects of these mutations on the divisions in more detail and test whether Wnt signaling acts in the GRP-1 or PIG-1 pathways. 3) Our analysis of GRP-1 and Wnt signaling indicates that cell signaling regulates asymmetric cell divisions. We will continue our EMS screens and begin RNAi screens to identify molecules that function in these signaling events, as well as molecules that act with HAM-1 and PIG-1.

描述（由申请人提供）：开发中的一个基本问题是如何指定细胞。阐明细胞类型规范的机制对于理解和最终治疗人类疾病至关重要，例如癌症，因为这一过程发生了改变。指定细胞类型的一种机制是不对称细胞分裂，其中细胞分裂产生两个具有不同命运的子细胞。细胞内不对称分子和细胞信号传导似乎都会使神经母细胞极化，但这两种机制之间缺乏联系。我们发现信号传导对于产生凋亡细胞和神经前体的某些不对称分裂至关重要，并已鉴定出在这些分裂中不对称分布的分子。我们研究的总体目标是了解细胞内在机制和信号传导如何调节这些分裂过程中产生的神经元的命运。该提案有三个目标。 1) 我们建议确定细胞粘附素 GRP-1 如何调节不对称细胞分裂。我们的模型提出 GRP-1 在 V5 中发挥作用，调节 V5 和不对称分裂神经母细胞之间的信号传导，我们将针对需要 GRP-1 功能的几个分裂严格测试这个想法。我们将测试PI3K调节GRP-1并通过ARF-1和ARF-6介导其作用的模型。 GRP-1 令人惊讶地定位于细胞核，提出了细胞粘附素可能在那里发挥作用的有趣可能性，我们将询问 GRP-1 是否在细胞核中发挥其功能。最后，我们将研究 RNG-1 和 CNT-2，这两个可能在 GRP-1 途径中发挥作用的分子。 2）我们建议确定Wnts如何调节Q神经母细胞的不对称分裂，这也需要PIG-1和GRP-1功能。我们的初步实验表明，三个 Wnt 和两个 Frizzled 受体参与了这些分裂。我们将测试其余 Wnt 和 Wnt 受体的作用，更详细地描述这些突变对分裂的影响，并测试 Wnt 信号传导是否在 GRP-1 或 PIG-1 途径中起作用。 3) 我们对 GRP-1 和 Wnt 信号传导的分析表明细胞信号传导调节不对称细胞分裂。我们将继续我们的 EMS 筛选并开始 RNAi 筛选，以识别在这些信号事件中起作用的分子，以及与 HAM-1 和 PIG-1 一起作用的分子。