Intercellular Communication and Oocyte Polarity

描述（由申请人提供）：Notch介导的细胞-细胞通讯对许多发育和病理过程至关重要- Notch信号的失调通常与发育缺陷，癌症和其他人类疾病有关。在许多细胞类型中，Notch通路的活性必须被微调到最佳水平——杂合突变体的细微变化（单倍不全）可能导致严重的发育问题，如异常的t细胞和血管发育。研究Notch调控的一个极好的模型是果蝇卵室，其中Notch在介导生殖系细胞和体细胞衍生的卵泡上皮细胞（滤泡细胞）之间的相互作用中起着核心作用，这在卵母细胞极性的建立中至关重要。我们实验室和其他人的研究表明，Notch受到microrna的严格时间调控和Hippo （Hpo）通路的空间调控。目前尚不清楚这些时间和空间调控模式是如何在分子水平上实现的，以及Notch效应是如何通过下游转录因子（TFs）介导以确保适当的体细胞-种系通信的。这里提出的工作将集中于回答这些问题。我们的长期目标是破译协调体细胞和生殖细胞发育的信号网络，以建立卵子的轴向模式，并进一步利用该模型系统阐明信号通路如何相互作用以调节正常和癌症发育中的细胞行为。我们的直接目标是确定Notch信号是如何通过时间和空间线索来调节卵泡细胞上皮的模式，以实现适当的体细胞-种系通信。我们的中心假设是，卵泡细胞中Notch激活的精确模式是由特定的microRNA通过配体Delta和Hpo途径通过共享因子调节的。Notch信号活性随后由下游tf后见明和Broad介导，以控制对卵母细胞极性很重要的后续卵泡细胞行为。我们计划测试我们的中心假设，从而通过追求以下三个具体目标来实现应用程序的目标：1。以确定Hpo和Notch信号如何相互作用以调节卵泡细胞分化。2. 确定microrna如何调节卵泡细胞中Notch信号的时间。3. 确定Notch信号在卵泡细胞中是如何通过后见之明和Broad传递的。这些研究预计将产生重要的积极影响，因为Notch通路及其调控因子大多是进化保守的，并已被证明与许多类型的人类疾病有关。了解这些调控机制将为Notch调控网络的复杂性提供新的见解，有助于寻找Notch相关疾病的新治疗途径，因此具有重要的生物医学意义。

DESCRIPTION (provided by applicant): Notch-mediated cell-cell communication is crucial for many developmental and pathological processes- dysregulation of Notch signaling is frequently linked to developmental defects, cancer and other human diseases. Notch pathway activity must be fine-tuned to optimum levels in many cell types-subtle changes in heterozygous mutants (haploinsufficiency) can lead to serious developmental problems such as aberrant T-cell and vascular development. An excellent model for the study of Notch regulation is the Drosophila egg chamber, in which Notch plays a central role in mediating the interaction between the germ-line cells and somatically derived follicular epithelial cells (follicle cells), wich is essential in the establishment of oocyte polarity. Studies from our laboratory and others have revealed that Notch is subject to strict temporal regulation by microRNAs and spatial regulation by the Hippo (Hpo) pathway. What is not known is how these temporal and spatial regulatory patterns are achieved at the molecular level and how Notch effects are mediated by downstream transcription factors (TFs) to ensure proper soma-germ line communication. The work proposed here will focus on answering these questions. Our long term goal is to decipher the signaling network that coordinates somatic and germline cell development to establish the axial pattern of the egg, and further use this model system to elucidate how signaling pathways interact to regulate cellular behaviors in normal and cancer development. Our immediate goal is to determine how Notch signaling is regulated by temporal and spatial cues to pattern the follicle cell epithelium for proper soma-germ line communication. Our central hypothesis is that precise patterning of Notch activation in follicle cells is regulated by a specific microRNA through the ligand Delta and by the Hpo pathway through a shared factor. Notch signaling activity is then mediated by downstream TFs Hindsight and Broad to control subsequent follicle-cell behaviors that are important for oocye polarity. We plan to test our central hypothesis and, thereby, to accomplish the objectives of the application by pursuing the following three specific aims: 1. to determine how Hpo and Notch signaling interact to regulate follicle-cell differentiation. 2. To determine how microRNAs regulate the timing of Notch signaling in follicle cells. 3. To determine how Notch signaling is transmitted by Hindsight and Broad in follicle cells. These studies are expected to have an important positive impact because the Notch pathway and its regulators are mostly evolutionarily conserved and have been shown to be related to many types of human diseases. Understanding these regulatory mechanisms will provide new insights into the complexity of the Notch regulation network aid the search for new therapeutic avenues for Notch-related diseases and is therefore of significant biomedical relevance.