Department of Biology, University of Padova, Padova, Italy.
Matrix Biol. 2010 Jan;29(1):43-50. doi: 10.1016/j.matbio.2009.09.001. Epub 2009 Sep 15.
Sulfated glycosaminoglycan chains of extracellular matrix and cell membrane-tethered proteoglycans exert specific cellular functions by interacting with a broad spectrum of morphogens and growth factors. In humans, a congenital impaired catabolism of sulfated glycosaminoglycans is associated with severe metabolic disorders. Here, we report on the identification and characterization of a zebrafish iduronate sulfatase orthologue. By knocking down its function with antisense morpholino oligos, we demonstrate that iduronate sulfatase plays a critical role during early vertebrate development and its downregulation may be responsible for severe developmental defects, including a misshapen trunk and abnormal craniofacial cartilages. We show that the altered cartilage patterning is mediated by depauperation of sox10-expressing neural crest cell precursors. Through the application of a transactivation reporter assay, we also provide a molecular proof that increased TGFbeta (Transforming Growth Factor beta) signalling is tightly associated with downregulation of iduronate sulfatase function. Our results provide an insight into the early biological impairments underlying the Hunter syndrome and suggest the use of zebrafish as a novel tool to better understand lysosomal storage disorder pathogenesis.
细胞外基质的硫酸化糖胺聚糖链和细胞膜结合的蛋白聚糖通过与广泛的形态发生素和生长因子相互作用发挥特定的细胞功能。在人类中，先天性硫酸化糖胺聚糖代谢受损与严重的代谢紊乱有关。在这里，我们报告了斑马鱼艾杜糖醛酸硫酸酯酶同源物的鉴定和表征。通过用反义形态发生素寡核苷酸敲低其功能，我们证明艾杜糖醛酸硫酸酯酶在早期脊椎动物发育中起着关键作用，其下调可能是严重发育缺陷的原因，包括畸形的躯干和异常的颅面软骨。我们表明，改变的软骨模式是由 Sox10 表达的神经嵴细胞前体的贫化介导的。通过应用转激活报告基因检测，我们还提供了分子证据，表明 TGFβ（转化生长因子β）信号的增加与艾杜糖醛酸硫酸酯酶功能的下调密切相关。我们的研究结果深入了解亨特综合征的早期生物学损伤，并表明使用斑马鱼作为一种新的工具来更好地理解溶酶体储存障碍的发病机制。
