RUI: Characterization of Notch Cis-Inhibitory Sequences in the Serrate Ligand of Drosophila Melanogaster

Notch信号系统是一种细胞间的通讯机制，几乎存在于所有多细胞生物体中，并允许发育中的细胞获得其特殊的细胞类型(神经元、肌肉、消化、生殖等)。这一系统有许多组成部分，其中两个是本提案的主要重点。这些是Notch信号受体分子和Serrate配体，能够与Notch受体活性相互作用并影响其活性。当这些分子在相邻细胞上表达时，Serrate配体可以激活受体，导致不同类型细胞的形成。当这些分子在同一细胞上共表达时，锯齿状物也可以抑制受体，防止这些细胞接收Notch信号并形成独特的细胞类型。这项建议调查了负责抑制Notch受体的Serrate配体的特定区域和属性，从而研究了控制细胞特化的关键机制方面。这项工作利用锯齿分子的定向分子遗传突变以及这些突变形式随后在果蝇中的表达来研究它们对Notch信号的影响。预计结果将充分定义和表征Serrate的区域，这些区域赋予Notch受体配体的抑制特性，并可能定义Notch激活所必需的区域。Notch系统成分在进化上的保守性使得这项研究的结果可以非常广泛地应用于脊椎动物中的同源分子。此外，这项研究将扩大对多细胞动物细胞分化控制的理解，包括干细胞分化机制。这项研究将由本科生研究人员进行，为这些学生提供分子和遗传工具方面的强大背景，为后续的专业培训和发展提供支持。

The Notch signaling system is a cell-to-cell communication mechanism that is found in virtually all multicellular organisms and allows developing cells to acquire their specialized cellular types (neuronal, muscular, digestive, reproductive, etc.). This system has many components, two of which are the main focus of this proposal. These are the Notch signal receptor molecule and the Serrate ligand that is capable of interacting with and affecting Notch receptor activity. The Serrate ligand can activate the receptor when these molecules are expressed on adjacent cells leading to the formation of different cell types. Serrate can also inhibit the receptor when these molecules are co-expressed on the same cell, preventing such cells from receiving a Notch signal and forming distinctive cellular types. This proposal investigates the specific regions and properties of the Serrate ligand that are responsible for inhibiting the Notch receptor hence investigating a crucial mechanistic aspect for controlling cellular specialization. The work utilizes targeted molecular-genetic mutation of the Serrate molecule with subsequent expression of these mutated forms in the fruit fly to investigate their effects on Notch signaling. The outcomes are expected to fully define and characterize the regions of Serrate that confer the inhibitory property of the ligand onto the Notch receptor and potentially define regions essential for Notch activation. The evolutionarily conserved nature of Notch system components allows for very broad applicability of the findings of this study to the homologous molecules in vertebrates. Further, this study will extend the understanding of cellular differentiation control in multicellular animals including stem cell differentiation mechanisms. The study will be conducted by undergraduate researchers providing these students with a strong background in molecular and genetic tools for subsequent professional training and development.