Apical extracellular matrix regulates tracheal tube development

The National Institute of General Medical Sciences awarded Oakland University $573,750 on June 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate how the apical extracellular matrix regulates tracheal tube development in Drosophila.

The research addresses fundamental mechanisms of tube morphogenesis by examining taenidial folds, stable apical extracellular matrix structures in the Drosophila trachea that are functionally similar to mammalian systems including pulmonary surfactant and mucin-rich coatings. The investigator has developed OSI18+20 double mutants using CRISPR in which taenidial folds are selectively disrupted, providing a genetic model to determine how these structures regulate tube morphogenesis during development. Early findings indicate that taenidial folds actively regulate tube morphogenesis beyond their traditional role as structural supports, with double mutants exhibiting early defects in tube morphology, apical actin organization, and mechanotransduction pathway activation before tube collapse occurs. Understanding these mechanisms addresses a gap relevant to diseases caused by disrupted apical extracellular matrices, including pulmonary airway malformations and polycystic kidney disease.

The award is classified as a Project Grant. Performance occurs in Rochester, Michigan, with the period of performance running through May 31, 2029.

Abstract

Proper tube morphology is essential for the function of organs such as the lungs, kidneys, and blood vessels. A key structural feature of these systems is the stable apical extracellular matrix (aecm)-a specialized layer of protein proteoglycans, and lipids secreted by organ-forming cells. This layer lines the luminal (inner) surface of tubes. Stable aecms, including pulmonary surfactant and mucin-rich coatings, are critical for organ integrity and function, and their disruption is linked to diseases such as pulmonary airway malformations and polycystic kidney disease. In the drosophila trachea, the stable aecm consists of taenidial folds: spiral, ridge-like structures that line the luminal surface and are functionally similar to aecms found in mammalian systems. Despite their biological importance, how stable aecms regulate tube morphogenesis remains poorly understood. Addressing this GAP is key to revealing the fundamental mechanisms of tube formation and gaining insight into diseases caused by disrupted aecms. The objective of this application is to determine how taenidial folds, the stable aecm in the drosophila trachea, regulate tube morphogenesis during development. We recently identified two osiris proteins, OSI18 and OSI20, that specifically localize to taenidial folds using antibodies we generated. Using crispr, we created OSI18+20 double mutants in which taenidial folds are selectively disrupted. This provides a unique genetic model to investigate how taenidial folds-and more broadly, apical extracellular matrices (aecms)-regulate tube morphogenesis. Remarkably, these double mutants exhibit early defects in tube morphology, apical actin organization, and mechanotransduction pathway activation-well before tube collapse occurs. These findings indicate that taenidial folds actively regulate tube morphogenesis, beyond their traditional role as structural supports. We hypothesize that taenidial folds drive tube morphogenesis by activating apical mechanotransduction pathways, specifically the SRC-RHO-actin remodeling cascade. To test this, we will employ live imaging, immunostaining, genetic interaction analyses, and biochemical assays to define the role of taenidial folds in mechanotransduction and epithelial remodeling. This research will uncover a novel function for stable aecms as active, instructive regulators of tissue morphogenesis. Given their conserved presence in tubular organs across species, studying how taenidial folds guide epithelial remodeling during drosophila tracheal development will reveal broadly applicable principles of tubulogenesis. These insights will enhance our understanding of the developmental basis of human diseases affecting the lungs, kidneys, and vasculature. Aligned with the NIH R15 mission, this project will support an undergraduate-centered research program at oakland university, providing students with hands-on training in developmental biology, genetics, live imaging, and molecular techniques-preparing them for future careers in biomedical research.