Friday, May 9, 2025
5/9/2025
Mechanisms of Cell Communication in Animal Development - The broad objective of my research program is to unravel the fundamental rules and mechanisms governing cell-cell communication that underlie the formation of complex tissue patterns in animals. The precision with which cells regulate levels, timing, location, and directionality of long-range signal communication is vital for animal development. Any deviation from this control mechanism can lead to developmental anomalies and disease. While conventional models suggest that secreted signaling proteins passively diffuse through the extracellular space to convey information from cell to cell, my previous research laid the foundation for understanding a more precise form of extracellular signal dispersion by characterizing a novel asymmetric 'direct delivery' mechanism orchestrated by specialized actin-rich signaling filopodia known as cytonemes. Cytonemes are thin actin-based membrane protrusions that enable cells to physically interact with each other and send or receive signals through their contact sites in a polarized manner. To unravel the mechanisms that control cytonemes and cytoneme-mediated signaling, we focus on a developing tracheal epithelial tube and a muscle stem cell niche in Drosophila and investigate intercellular communication of Fibroblast Growth Factor (FGF), an essential signaling protein in metazoan development. We discovered that cytonemes emanating from these tissues exchange FGF through their contact sites in a highly polarized manner. We found that the number and directionality of these cytonemes are precisely regulated by the intricate FGF signaling feedback mechanisms. This self-regulatory feature of FGF signaling allows it to control its own levels and spatial range by modulating the formation of FGF-receiving cytonemes. These findings also shed light on the self-regulatory attribute of cytonemes that can shape signaling asymmetry and promote self-organization. Furthermore, we discovered a series of post-translational enzymatic cleavage and lipid modification of an FGF. Surprisingly, these modifications prepare FGF for cytoneme-mediated exchange by controlling its intracellular trafficking, membrane-anchored display, and subsequent release of the membrane-anchored FGF from the cell surface via an intricate enzymatic shedding mechanism. These discoveries have opened up new avenues of investigation into the regulatory mechanisms that selectively release lipid-modified signals like FGF through the cytoneme contact sites and thereby control the location, timing, and levels of signal exchange. Building on these significant leads and leveraging our expertise in genetics, molecular and cell biology, and high-resolution imaging, our future research aims to delve deeper into the intricate molecular and cellular mechanisms governing cytoneme-mediated polarized signaling and self-organization. Given the conservation of the essential signaling mechanisms and the critical significance of asymmetric signaling across organisms, this research will have profound implications for both developmental biology and disease research and will offer a conceptual framework for future tissue engineering.
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