Apical extracellular matrix regulates tracheal tube development
openNIGMS - National Institute of General Medical Sciences
Project Summary
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.
Up to $574K
health research