Venero Galanternik Marina, Lush Mark E, Piotrowski Tatjana
Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA.
Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA.
Dev Biol. 2016 Nov 15;419(2):321-335. doi: 10.1016/j.ydbio.2016.09.002. Epub 2016 Sep 15.
Collective cell migration is an essential process during embryonic development and diseases such as cancer, and still much remains to be learned about how cell intrinsic and environmental cues are coordinated to guide cells to their targets. The migration-dependent development of the zebrafish sensory lateral line proves to be an excellent model to study how proteoglycans control collective cell migration in a vertebrate. Proteoglycans are extracellular matrix glycoproteins essential for the control of several signaling pathways including Wnt/β-catenin, Fgf, BMP and Hh. In the lateral line primordium the modified sugar chains on proteoglycans are important regulators of cell polarity, ligand distribution and Fgf signaling. At least five proteoglycans show distinct expression patterns in the primordium; however, their individual functions have not been studied. Here, we describe the function of glypican4 during zebrafish lateral line development. glypican4 is expressed in neuromasts, interneuromast cells and muscle cells underlying the lateral line. knypek/glypican4 mutants show severe primordium migration defects and the primordium often U-turns and migrates back toward the head. Our analysis shows that Glypican4 regulates the feedback loop between Wnt/β-catenin/Fgf signaling in the primordium redundantly with other Heparan Sulfate Proteoglycans. In addition, the primordium migration defect is caused non-cell autonomously by the loss of cxcl12a-expressing muscle precursors along the myoseptum via downregulation of Hh. Our results show that glypican4 has distinct functions in primordium cells and cells in the environment and that both of these functions are essential for collective cell migration.
集体细胞迁移是胚胎发育以及癌症等疾病过程中的一个重要过程，然而，关于细胞内在信号和环境信号如何协同作用以引导细胞到达目标，仍有许多有待了解的地方。斑马鱼感觉侧线依赖迁移的发育过程被证明是研究蛋白聚糖如何在脊椎动物中控制集体细胞迁移的一个优秀模型。蛋白聚糖是细胞外基质糖蛋白，对于控制包括Wnt/β-连环蛋白、Fgf、BMP和Hh在内的多种信号通路至关重要。在侧线原基中，蛋白聚糖上的修饰糖链是细胞极性、配体分布和Fgf信号的重要调节因子。至少有五种蛋白聚糖在原基中呈现出不同的表达模式；然而，它们各自的功能尚未得到研究。在这里，我们描述了glypican4在斑马鱼侧线发育过程中的功能。glypican4在侧线下方的神经丘、神经丘间细胞和肌肉细胞中表达。knypek/glypican4突变体表现出严重的原基迁移缺陷，原基常常掉头并向头部回移。我们的分析表明，Glypican4与其他硫酸乙酰肝素蛋白聚糖一起，在原基中冗余调节Wnt/β-连环蛋白/Fgf信号之间的反馈回路。此外，原基迁移缺陷是由沿着肌隔表达cxcl12a的肌肉前体细胞通过下调Hh而非细胞自主丧失所导致的。我们的结果表明，glypican4在原基细胞和周围环境细胞中具有不同的功能，并且这两种功能对于集体细胞迁移都是必不可少的。
