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.
The proposed project uses the Drosophila egg chamber as a model system to investigate how cells communicate to regulate oocyte polarity and to determine how spatial and temporal patterns of Notch signaling are controlled by the Hippo pathway and microRNAs, respectively. These studies will provide insights into the regulatory role of microRNAs and evolutionarily conserved Notch and Hippo signaling in normal development and under abnormal conditions such as tumorigenesis.
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