Genes that influence LIN-12/Notch Activity in C. elegans

LIN-12/Notch蛋白是一种受体，介导细胞与细胞之间的相互作用，决定细胞的命运 动物发育。对LIN-12/Notch蛋白的研究直接关系到对分子的理解 两种严重而常见的人类疾病的潜在机制。LIN-12/Notch的本构活化 _roteins与人类患者和哺乳动物的某些癌症的发生有关 模型，并且LIN-12/Notch信号转导通路的关键成分PresenUin的活性是 对阿尔茨海默病的发展至关重要。其他不太常见的疾病也与此有关。 LIN-12/Notch途径组分有异常。 我们在线虫LIN-12上的工作有助于目前对保守性的理解 LIN-12/Notch蛋白的发育作用及其分子机制这项提案涉及的是 识别和表征影响线虫LIN-12活性的新基因。我们的第一个明确目标 基于对相关表型的抑制，在经过验证的基因筛查上包含了新的变异 具有结构性LIN-12激活[LIN-12(D)等位基因]。我们的第二个具体目标是关于基本的 新SEL[LIN-12抑制子/增强子]基因的特征，以及我们的第三个特定目标涉及 了解我们识别的新基因是如何协同工作的。后两个具体目标涉及 外阴前体细胞规范中LIN-12介导的侧向信号传递。第四个目标是 在这一信号事件中识别和表征LIN-12的配体，并关注第五个目标 描述了一个基因，该基因可能参与RAS介导的外阴诱导和 LIN-12介导的侧向信号传递。 当这些具体目标完成后，我们希望确定保守的成分和 动物LIN-12/Notch信号调控和执行的基本机制 发展。

LIN-12/Notch proteins are receptors that mediate cell-cell interactions that specify cell fate during animal development. Studies of LIN-12/Notch proteins are directly relevant to understanding the molecular mechanisms underlying two serious and common human diseases. Constitutive activation of LIN-12/Notch _roteins has been associated with the development of certain cancers in human patients and in mammalian models, and the activity of a key component of the LIN-12/Notch signal transduction pathway, presenUin, is central to the development of Alzheimer's disease. Other, less common, diseases have also been associated with aberrations in LIN-12/Notch pathway components. Our work on lin-12 in C. elegans has contributed to the current state of understanding of conserved developmental roles and molecular mechanisms of LIN-12/Notch proteins. This proposal is concerned with identifying and characterizing new genes that influence lin-12 activity in C. elegans. Our first specific aim encompasses new variations on a proven genetic screen, based on suppression of phenotypes associated with constitutive lin-12 activation [lin-12(d) alleles]. Our second specific aim is concerned with the basic characterization of new sel [suppressor/enhancer of lin-12] genes, and our third specific aim is concerned with understanding how the new genes we identify work together. The last two specific aims are involved with the LIN-12-mediated lateral signalling during vulval precursor cell specification. The fourth aim is concerned with identifying and characterizing the ligand for LIN-12 in this signalling event, and the fifth aim is concerned with characterizing a gene that may be involved in the interplay between Ras-mediated vulval induction and LIN-12-mediated lateral signalling. When these specific aims are completed, we hope to have identified conserved components and illuminated fundamental mechanisms of the regulation and execution of LIN-12/Notch signalling in animal development.