Regulation of Drosophila Midgut Development and Homeostasis by Dietary Lipids

[摘要] Tissue homeostasis involves a complex balance of developmental signals and environmental cues that dictate stem cell function. The second chapter of this dissertation describes how dietary lipids control enteroendocrine cell production from Drosophila posterior midgut stem cells.By modulating the diet of newly eclosed flies, I found that dietary cholesterol influences new intestinal cell differentiation in an Hr96-dependent manner by altering the level and duration of Notch signaling.Exogenous lipids modulate Delta ligand and Notch extracellular domain stability and alter their trafficking in endosomal vesicles.Lipid-modulated Notch signaling occurs in other nutrient-dependent tissues, suggesting that Delta trafficking in many cells is sensitive to cellular sterol levels.These diet-mediated alterations in young animals contribute to a metabolic program that persists after the diet changes.A low sterol diet also slows the proliferation of enteroendocrine tumors initiated by Notch pathway disruption. In the third chapter I contrast the regions of the larval and adult midgut, and describe how the adult midgut progenitors divide during pupation to create the foundation for the adult midgut. I induced a lineage mark at varying times during development, and then observed the developed clones later to show that midgut development occurs in an anterior to posterior manner. I also present preliminary data that demonstrates a role for the nuclear receptor and nutrient sensor, HNF4, in midgut development. These results provide a foundation for future work analyzing the role of other nutrients in midgut development. This is the first study to identify a specific dietary nutrient that can modify a key intercellular signaling pathway to shift stem cell differentiation and cause lasting changes in tissue structure and physiology. This work further identifies a developmental window when the midgut is especially susceptible to influences by dietary metabolites, and demonstrates a way to use this developmental window to study the influence of metabolites on cell signaling pathways. An understanding how diet affects these pathways will be a critical asset in developing disease treatments and understanding the implications of metabolic disorders.

[发布机构] Johns Hopkins University

[效力级别] Development

[关键词] Drosophila;Development;Biology