Biology Department, Colgate University, Hamilton, NY, United States.
Dev Biol. 2013 Jun 15;378(2):107-21. doi: 10.1016/j.ydbio.2013.04.002. Epub 2013 Apr 11.
Heparan sulfate proteoglycans (HSPGs) are glycosylated extracellular or membrane-associated proteins. Their unbranched heparan sulfate (HS) disaccharide chains interact with many growth factors and receptors, modifying their activity or diffusion. The pattern of HS sulfation can be altered by the enzymes Sulf1 and Sulf2, secreted extracellular 6-O endosulfatases, which remove specific sulfate groups from HS. Modification by Sulf enzymes changes the binding affinity of HS for protein such as ligands and receptors, affecting growth factor gradients and activities. The precise expression of these sulfatases are thought to be necessary for normal development. We have examined the role of the sulf1 gene in trunk development of zebrafish embryos. sulf1 is expressed in the developing trunk musculature and as well as in midline structures such as the notochord, floorplate and hypochord. Knockdown of sulf1 with antisense morpholinos results in poor differentiation of the somitic trunk muscle, loss of the horizontal myoseptum, lack of pigmentation along the mediolateral stripe, and improper migration of the lateral line primordium. sulf1 knockdown results in a decrease in the number of Pax7-expressing dermomyotome cells, particularly along the midline where the horizontal myoseptum develops. It also leads to decreased sdf1/cxcl12 expression along the mediolateral trunk musculature. Both the Pax7 and cxcl12 expression can be restored by inhibition pharmacological inhibition of BMP signaling, which also restores formation of the myoseptum, fast muscle development, and pigmentation patterning. Lateral line migration and neuromast deposition depend on sdf1/cxcl12 and FGF signaling respectively, both of which are disrupted in sulf1 morphants. Pharmacological activation of FGF signaling can rescue the spacing of neuromast deposition in these fish. Together this data indicate that sulf1 plays a crucial role in modulating both BMP and FGF signaling along the developing myoseptum to coordinate the morphogenesis of trunk musculature, associated pigment cells, and lateral line neuromasts.
硫酸乙酰肝素蛋白聚糖（HSPGs）是糖基化的细胞外或膜相关蛋白。其未分支的硫酸乙酰肝素（HS）二糖链与许多生长因子和受体相互作用，改变它们的活性或扩散。HS 硫酸化的模式可以通过酶 Sulf1 和 Sulf2 改变，这两种酶是分泌的细胞外 6-O 内切硫酸酯酶，从 HS 中去除特定的硫酸基团。Sulf 酶的修饰改变了 HS 与配体和受体等蛋白的结合亲和力，影响生长因子梯度和活性。这些硫酸酯酶的精确表达被认为是正常发育所必需的。我们研究了 sulf1 基因在斑马鱼胚胎躯干发育中的作用。sulf1 在发育中的躯干肌肉以及脊索、基板和脊索下组织中表达。用反义 morpholino 敲低 sulf1 导致体节躯干肌肉分化不良、水平肌隔缺失、沿中侧条纹缺乏色素沉着以及侧线原基迁移不当。sulf1 敲低导致 Pax7 表达的真皮肌细胞数量减少，特别是在水平肌隔发育的中线处。它还导致沿中侧躯干肌肉的 sdf1/cxcl12 表达减少。Pax7 和 cxcl12 的表达都可以通过抑制 BMP 信号转导来恢复，这也恢复了肌隔的形成、快肌的发育和色素沉着模式。侧线迁移和神经嵴沉积分别依赖于 sdf1/cxcl12 和 FGF 信号，这两种信号在 sulf1 突变体中都被破坏。FGF 信号的药理学激活可以挽救这些鱼中神经嵴沉积的间隔。总的来说，这些数据表明 sulf1 在调节沿发育中的肌隔的 BMP 和 FGF 信号方面起着至关重要的作用，以协调躯干肌肉、相关色素细胞和侧线神经嵴的形态发生。
