Department of Developmental Biology, Stanford University School of Medicine, United States of America.
Department of Developmental Biology, Stanford University School of Medicine, United States of America; Howard Hughes Medical Institute, Stanford University School of Medicine, United States of America.
Bone. 2022 Feb;155:116263. doi: 10.1016/j.bone.2021.116263. Epub 2021 Nov 23.
Many key signaling molecules used to build tissues during embryonic development are re-activated at injury sites to stimulate tissue regeneration and repair. Bone morphogenetic proteins provide a classic example, but the mechanisms that lead to reactivation of BMPs following injury are still unknown. Previous studies have mapped a large "injury response element" (IRE) in the mouse Bmp5 gene that drives gene expression following bone fractures and other types of injury. Here we show that the large mouse IRE region is also activated in both zebrafish tail resection and mechanosensory hair cell injury models. Using the ability to test multiple constructs and image temporal and spatial dynamics following injury responses, we have narrowed the original size of the mouse IRE region by over 100 fold and identified a small 142 bp minimal enhancer that is rapidly induced in both mesenchymal and epithelial tissues after injury. These studies identify a small sequence that responds to evolutionarily conserved local signals in wounded tissues and suggest candidate pathways that contribute to BMP reactivation after injury.
许多在胚胎发育过程中用于构建组织的关键信号分子在损伤部位被重新激活,以刺激组织再生和修复。骨形态发生蛋白(BMPs)就是一个典型的例子,但导致损伤后 BMP 重新激活的机制仍不清楚。先前的研究已经在小鼠 Bmp5 基因中绘制了一个大型“损伤反应元件(IRE)”,该元件可在骨骨折和其他类型的损伤后驱动基因表达。在这里,我们表明,大型小鼠 IRE 区域也在斑马鱼尾部切除和机械感觉毛细胞损伤模型中被激活。利用能够测试多种构建体并在损伤反应后对时空动态进行成像的能力,我们将原始小鼠 IRE 区域的大小缩小了 100 多倍,并鉴定出一个小的 142bp 最小增强子,该增强子在损伤后迅速在间充质和上皮组织中诱导。这些研究鉴定出一个小序列,该序列可响应损伤组织中保守的局部信号,并提示候选途径有助于损伤后 BMP 的重新激活。