Department of Biochemistry and Molecular Biology, The University of Texas Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Curr Biol. 2009 Sep 15;19(17):1473-7. doi: 10.1016/j.cub.2009.07.019. Epub 2009 Jul 30.
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.
表皮细胞的迁移对于损伤后组织结构和功能的恢复至关重要。然而，相邻伤口的分化细胞如何感知伤口并呈现出运动表型的机制尚不清楚。在这里，我们表明，与血小板衍生生长因子（PDGF）和血管内皮生长因子（VEGF）受体相关的受体酪氨酸激酶（RTK）Pvr及其配体之一 Pvf1，是表皮伤口闭合所必需的。对缺乏 Pvr 或先前涉及幼虫伤口闭合的 Jun N-末端激酶（JNK）信号通路的伤口边缘细胞的形态比较表明，Pvr 信号导致伤口边缘的表皮细胞将基于肌动蛋白的细胞过程延伸到伤口间隙中，而 JNK 介导伤口边缘细胞的短暂去分化。遗传上位性实验进一步证实了 JNK 和 Pvr 信号通路平行作用的结论。组织特异性敲低和挽救实验表明，表皮衍生的 Pvf1 可能被隔离在血液中，组织损伤将血液来源的 Pvf1 暴露于伤口边缘表皮细胞上的 Pvr 受体，并启动细胞过程向伤口间隙延伸。这些结果揭示了一种感知组织损伤的新机制，并表明 PDGF/VEGF 配体和受体可能在表皮伤口闭合中发挥保守的自分泌作用。
