Olson Lorin E, Soriano Philippe
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Dev Cell. 2009 Feb;16(2):303-13. doi: 10.1016/j.devcel.2008.12.003.
PDGF signaling regulates the development of mesenchymal cell types in the embryo and in the adult, but the role of receptor activation in tissue homeostasis has not been investigated. We have generated conditional knockin mice with mutations in PDGFRalpha that drive increased kinase activity under the control of the endogenous PDGFRalpha promoter. In embryos, increased PDGFRalpha signaling leads to hyperplasia of stromal fibroblasts, which disturbs normal smooth muscle tissue in radially patterned organs. In adult mice, elevated PDGFRalpha signaling also increases connective tissue growth, leading to a progressive fibrosis phenotype in multiple organs. Increased PDGFRalpha signaling in an Ink4a/Arf-deficient genetic background leads to accelerated fibrosis, suggesting a new role for tumor suppressors in attenuating fibrotic diseases. These results highlight the role of PDGFRalpha in normal connective tissue development and homeostasis and demonstrate a pivotal role for PDGFRalpha signaling in systemic fibrosis diseases.
血小板衍生生长因子（PDGF）信号传导调控胚胎和成体中间充质细胞类型的发育，但受体激活在组织稳态中的作用尚未得到研究。我们构建了条件性基因敲入小鼠，其PDGFRα发生突变，在内源性PDGFRα启动子的控制下驱动激酶活性增加。在胚胎中，PDGFRα信号增强导致基质成纤维细胞增生，扰乱了径向模式器官中的正常平滑肌组织。在成年小鼠中，升高的PDGFRα信号也会增加结缔组织生长，导致多个器官出现进行性纤维化表型。在Ink4a/Arf基因缺陷的遗传背景下，PDGFRα信号增强导致纤维化加速，提示肿瘤抑制因子在减轻纤维化疾病中具有新作用。这些结果突出了PDGFRα在正常结缔组织发育和稳态中的作用，并证明了PDGFRα信号在系统性纤维化疾病中的关键作用。
