Sunday, May 18, 2025
5/18/2025
Apical extracellular matrix during organ formation - PROJECT SUMMARY Many organs in the human body, such as the kidneys, lungs, and digestive organs, are organized as three-dimensional tubular structures. Abnormal tube size leads to defects in organ formation, such as polycystic kidney disease and pulmonary agenesis (underdeveloped lungs). There is increasing evidence that the apical extracellular matrix (aECM), the extracellular layer on the apical (luminal) side of epithelia, actively contributes to epithelial morphogenesis. Studies in C. elegans and Drosophila have identified the aECM as a critical regulator of tube expansion and elongation and have shown that post-translational modifications of the aECM are essential for correct tube dimensions. However, very little is known about the structural components and biological functions of aECM, and the mechanisms of tube size control by aECM remain largely unknown. The Drosophila embryonic salivary gland (SG) is an excellent system to study aECM and tube dimensional control. From our pilot screen in the Drosophila embryonic salivary gland (SG) to identify key enzymes that affect SG morphology, we have identified Papss, an enzyme synthesizing an activated sulfate donor compound, as a critical regulator of SG lumen expansion. Sulfation is one of the most common post-translational modifications of ECM components. Defects in sulfation lead to many human diseases, such as bone and joint abnormalities and eye disorders. How sulfation affects the formation of internal tubular organs is unknown. Our initial analysis revealed that Papss mutants have a defective, condensed aECM in the SG, which is associated with disrupted Golgi structure. We also identified zona pellucida (ZP) proteins and mucins as critical aECM components for proper SG lumen morphology. In the proposed studies, we will elucidate the mechanisms by which the aECM and its modification regulate the dimensions of tubular organs and to identify/characterize key aECM components. First, we will elucidate the mechanism by which Papss regulates the aECM. Second, we will dissect the role of ZP proteins and mucins in the SG aECM. The powerful genetics combined with state-of-the-art microscopy make the Drosophila SG an excellent model to address these questions. Members of my lab have expertise in genetics, cell and developmental biology, and advanced microscopy techniques, and we are well equipped with the necessary instrumentation. The proposed work will help elucidate how organ precursor cells generate and modulate their extracellular environment, and how the extracellular environment influences tissue morphogenetic processes. We expect these studies to be generally applicable to the development and function of human organs.
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