Cell-cell communication mediated by fluid flows - Project Summary Cells communicate not only through chemical signals but also through physical forces such as fluid flows. These flow-based signals are critical for shaping the body during development, maintaining tissue function, and preventing disease. Yet, despite their ubiquity and importance, the mechanisms by which cells generate, sense, and respond to flow-derived signals remain largely unexplored. Our research program investigates the fundamental biology of flow signaling, focusing on how motile cilia generate extracellular flows, how sensory cells detect hydrodynamic cues, and how these signals are transduced into gene expression changes and cellular behaviors that drive tissue morphogenesis. Zebrafish offer a uniquely powerful system to investigate these questions, thanks to their optical clarity, genetic tractability, and distributed ciliated tissues. In recent work, we have shown that the timing of cilia motility, specifically how quickly cilia begin to beat during development, profoundly influences patterning and morphogenetic outcomes. Our studies of the dynein arm assembly factor Daw1 defined a new class of ciliopathy in which left-right organ asymmetry is disrupted due to delayed, rather than absent, cilia motility. We also identified Urotensin-related peptides as flow-responsive effectors required to maintain spine morphology during growth, establishing vertebrate models that link impaired flow signaling to spinal deformity. Most recently, we discovered how motile cilia in the spinal canal assemble the Reissner fiber (RF), a dynamic extracellular thread long hypothesized to control body shape. We found that motile cilia remodel secreted SCO-spondin into stretched fibrils, which twist and bundle together to form the RF, revealing a new mechanism by which intracellular motors shape extracellular architecture and raising key questions about how the RF organizes signaling and morphogenesis across tissues. In the next phase of this work, we will determine: (1) how the flow-responsive RF mediates chemical and mechanical signaling during body axis morphogenesis, and (2) how its structure and dynamics contribute to multi-tissue morphogenesis. In parallel, we have launched a systematic effort to characterize the roles of microtubule inner proteins (MIPs), a newly discovered class of largely unstudied proteins that reside within the ciliary microtubule lumen. This work will open new frontiers in motile ciliary biology and provide insight into how the architecture of the axoneme regulates cilia function and flow signaling. Together, our research will illuminate how flow-derived signals are generated and integrated with other inputs to sculpt the vertebrate body. These studies will generate foundational biological knowledge and new disease models relevant to birth defects, spine disorders, and other flow-related pathologies.
