Thursday, November 21, 2024
11/21/2024
Project Summary Cells can detect external fluid flows across their surface. Such flows, and the flow signaling events they induce, are critical for organ development, homeostasis, cancer dissemination, and host-microbe interactions, yet we know little about how cells sense and respond to their hydrodynamic environment. This research program aims to reveal fundamental mechanisms by which cells communicate through fluid flows. Specifically, we investigate how cells generate and sense fluid flows, and how sensory cells respond to flow-derived signals. To generate new fundamental knowledge about flow signaling, we use the well-established and highly tractable left-right patterning system of zebrafish embryos. In this system, which is amenable to genetic perturbation as well as high-resolution and quantitative imaging, a flow signal represses the expression of a key target gene, dand5, in sensory cells. In our prior work, we discovered that Pkd1l1, a large Polycystin membrane protein, is critical for flow-induced dand5 repression. In one aspect of our proposed work, we will test our hypothesis that Pkd1l1 is a flow signal sensory component by determining the cell types, as well as sub-cellular site of action, in which Pkd1l1 functions downstream of flow signals. We also investigate the functional role of mechanosensitive domains within Pkd1l1 in flow-regulated signaling. In a second project, we address the major gap in understanding of how flow signals are transduced within sensory cells. This work will use our optimized CRISPR approaches to discover and validate new flow signal transduction machinery, something which will markedly expand our understanding of the mechanisms acting downstream of sensory events to transduce signals intracellularly. In a third project, we will use the known post-transcriptional repression of dand5 that occurs specifically on the left side downstream of the flow signal as a model for generating new knowledge of how sensory cells respond to flow signals. This includes determining the role of the 3’untranslated region and how RNA-binding proteins and microRNAs act downstream of flow signals to repress gene expression. This work will be aided by novel in vivo reporters we are developing which quantify flow signaling pathway outputs. Overall, this research will uncover novel mechanisms by which cells communicate through flow signals. While chemical signal transduction cascades (Hedgehog, Wnt, etc.) are widely studied, flow signaling pathways represent a new frontier, with many fundamental principles waiting to be discovered. Our work using the highly tractable left-right patterning system of zebrafish will reveal new principles of flow signal sensation and transduction, as well as how cells respond to flow signals. Since aberrant flow signals occur in many disease states, this will open new opportunities to improve human health.
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