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A blood-borne PDGF/VEGF-like ligand initiates wound-induced epidermal cell migration in Drosophila larvae.

ABSTRACT: Epidermal cell migration is critical for restoration of tissue structure and function after damage. However, the mechanisms by which differentiated cells neighboring the wound sense the wound and assume a motile phenotype remain unclear. Here, we show that Pvr, a receptor tyrosine kinase (RTK) related to platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors, and one of its ligands, Pvf1, are required for epidermal wound closure. Morphological comparison of wound-edge cells lacking Pvr or the Jun N-terminal kinase (JNK) signaling pathway previously implicated in larval wound closure suggests that Pvr signaling leads wound-margin epidermal cells to extend actin-based cell processes into the wound gap while JNK mediates transient dedifferentiation of cells at the wound margin. Genetic epistasis experiments reinforce the conclusion that the JNK and Pvr signaling pathways act in parallel. Tissue-specific knockdown and rescue experiments suggest that epidermally derived Pvf1 may be sequestered in the blood and that tissue damage exposes blood-borne Pvf1 to Pvr receptors on wound-edge epidermal cells and initiates the extension of cell processes into the wound gap. These results uncover a novel mechanism of sensing tissue damage and suggest that PDGF/VEGF ligands and receptors may play a conserved autocrine role in epidermal wound closure.

SUBMITTER: Wu Y

PROVIDER: S-EPMC2783944 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:How multifunctional cells such as macrophages interpret the different cues within their environment and undertake an appropriate response is a key question in developmental biology. Understanding how cues are prioritized is critical to answering this - both the clearance of apoptotic cells (efferocytosis) and the migration toward damaged tissue is dependent on macrophages being able to interpret and prioritize multiple chemoattractants, polarize, and then undertake an appropriate migratory response. Here, we investigate the role of Spitz, the cardinal Drosophila epidermal growth factor (EGF) ligand, in regulation of macrophage behavior in the developing fly embryo, using activated variants with differential diffusion properties. Our results show that misexpression of activated Spitz can impact macrophage polarity and lead to clustering of cells in a variant-specific manner, when expressed either in macrophages or the developing fly heart. Spitz can also alter macrophage distribution and perturb apoptotic cell clearance undertaken by these phagocytic cells without affecting the overall levels of apoptosis within the embryo. Expression of active Spitz, but not a membrane-bound variant, can also increase macrophage migration speeds and impair their inflammatory responses to injury. The fact that the presence of Spitz specifically undermines the recruitment of more distal cells to wound sites suggests that Spitz desensitizes macrophages to wounds or is able to compete for their attention where wound signals are weaker. Taken together these results suggest this molecule regulates macrophage migration and their ability to dispose of apoptotic cells. This work identifies a novel regulator of Drosophila macrophage function and provides insights into signal prioritization and integration in vivo. Given the importance of apoptotic cell clearance and inflammation in human disease, this work may help us to understand the role EGF ligands play in immune cell recruitment during development and at sites of disease pathology.

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A blood-borne PDGF/VEGF-like ligand initiates wound-induced epidermal cell migration in Drosophila larvae.

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