Intercellular Communication and Oocyte Polarity

描述(申请人提供)：Notch介导的细胞间通讯对许多发育和病理过程至关重要-Notch信号的失调经常与发育缺陷、癌症和其他人类疾病有关。Notch途径的活性必须在许多细胞类型中微调到最佳水平-杂合突变(单倍体不足)的细微变化可能会导致严重的发育问题，如T细胞和血管发育异常。研究Notch调控的一个很好的模型是果蝇卵室，在其中Notch在生殖系细胞和体细胞来源的滤泡上皮细胞(卵泡细胞)之间的相互作用中起着核心作用，这在卵子极性的建立中是必不可少的。我们实验室和其他实验室的研究表明，Notch受到microRNAs的严格时间调节和河马(Hpo)途径的空间调节。目前尚不清楚这些时空调控模式是如何在分子水平上实现的，以及Notch效应是如何由下游转录因子(TF)介导以确保适当的体细胞-胚系通讯的。这里提出的工作将集中在回答这些问题上。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，并进一步使用这个模型系统来阐明信号通路如何相互作用，调节正常和癌症发展中的细胞行为。我们的直接目标是确定Notch信号如何受时间和空间线索的调节，以形成适当的体细胞-生殖系通讯的毛囊细胞上皮。我们的中心假设是，毛囊细胞中Notch激活的精确模式是由一个特定的microRNA通过配体Delta调节的，并通过一个共同的因子受到HPO途径的调节。然后，Notch信号活性由下游的TF、后见之明和广度来调节，以控制后续的卵泡细胞行为，这些行为对卵细胞的极性是重要的。我们计划验证我们的中心假说，从而通过追求以下三个具体目标来实现应用的目标：1.确定HPO和Notch信号如何相互作用来调节卵泡细胞的分化。2.确定microRNAs如何调节卵泡细胞中Notch信号的时序。3.研究Notch信号在卵泡细胞中的后向传递和广向传递。这些研究有望产生重要的积极影响，因为Notch通路及其调节因子大多在进化上是保守的，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了解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.