Center for Regenerative Medicine, Harvard Stem Cell Institute, Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA.
Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Development. 2020 Jun 24;147(12):dev185389. doi: 10.1242/dev.185389.
Tendons and ligaments are crucial components of the musculoskeletal system, yet the pathways specifying these fates remain poorly defined. Through a screen of known bioactive chemicals in zebrafish, we identified a new pathway regulating tendon cell induction. We established that statin, through inhibition of the mevalonate pathway, causes an expansion of the tendon progenitor population. Co-expression and live imaging studies indicate that the expansion does not involve an increase in cell proliferation, but rather results from re-specification of cells from the neural crest-derived skeletal lineage. The effect on tendon cell expansion is specific to the geranylgeranylation branch of the mevalonate pathway and is mediated by inhibition of Rac activity. This work establishes a novel role for the mevalonate pathway and Rac activity in regulating specification of the tendon lineage.
肌腱和韧带是肌肉骨骼系统的关键组成部分，但指定这些命运的途径仍未得到很好的定义。通过对斑马鱼中已知生物活性化学物质的筛选，我们确定了一个新的通路来调节肌腱细胞的诱导。我们发现，他汀类药物通过抑制甲羟戊酸途径，导致肌腱祖细胞群体的扩张。共表达和实时成像研究表明，这种扩张不涉及细胞增殖的增加，而是源于来自神经嵴衍生的骨骼谱系的细胞的重新特化。甲羟戊酸途径的香叶酰基化分支和 Rac 活性的抑制对肌腱细胞扩增的影响具有特异性，这是由 Rac 活性的抑制介导的。这项工作确立了甲羟戊酸途径和 Rac 活性在调节肌腱谱系特化中的新作用。
