Nandadasa Sumeda, Foulcer Simon, Apte Suneel S
Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Matrix Biol. 2014 Apr;35:34-41. doi: 10.1016/j.matbio.2014.01.005. Epub 2014 Jan 18.
Embryonic development is an exceptionally dynamic process, requiring a provisional extracellular matrix that is amenable to rapid remodeling, and proteolytic or non-proteolytic mechanisms that can remodel the major components of this matrix. Versican is a chondroitin-sulfate proteoglycan that forms highly hydrated complexes with hyaluronan and is widely distributed in the provisional matrix of mammalian embryos. It has been extensively studied in the context of cardiovascular morphogenesis, neural crest cell migration and skeletal development. Analysis of Vcan transgenic mice has established the requirement for versican in cardiac development and its role in skeletogenesis. The ADAMTS family includes several versican-degrading proteases that are active during remodeling of the embryonic provisional matrix, especially during sculpting of versican-rich tissues. Versican is cleaved at specific peptide bonds by ADAMTS proteases, and the cleavage products are detectable by neo-epitope antibodies. Myocardial compaction, closure of the secondary palate (in which neural crest derived cells participate), endocardial cushion remodeling, myogenesis and interdigital web regression are developmental contexts in which ADAMTS-mediated versican proteolysis has been identified as a crucial requirement. ADAMTS proteases are expressed coordinately and function cooperatively in many of these contexts. In addition to versican clearance, ADAMTS proteases generate a bioactive versican fragment containing the N-terminal G1 domain, which we have named versikine. This review promotes the view that the embryonic extracellular matrix has evolved not only to provide a permissive environment for embryo growth and morphogenesis, but through its dissolution to influence and regulate cellular processes.
胚胎发育是一个异常动态的过程，需要一个易于快速重塑的临时细胞外基质，以及能够重塑该基质主要成分的蛋白水解或非蛋白水解机制。多功能蛋白聚糖是一种硫酸软骨素蛋白聚糖，它与透明质酸形成高度水合的复合物，并广泛分布于哺乳动物胚胎的临时基质中。它在心血管形态发生、神经嵴细胞迁移和骨骼发育等方面已得到广泛研究。对Vcan转基因小鼠的分析已确定多功能蛋白聚糖在心脏发育中的需求及其在骨骼发生中的作用。ADAMTS家族包括几种在胚胎临时基质重塑过程中，尤其是在富含多功能蛋白聚糖的组织塑形过程中具有活性的多功能蛋白聚糖降解蛋白酶。多功能蛋白聚糖被ADAMTS蛋白酶在特定肽键处切割，切割产物可通过新表位抗体检测到。心肌致密化、继发腭闭合（神经嵴衍生细胞参与其中）、心内膜垫重塑、肌发生和指间蹼退化等发育过程中，ADAMTS介导的多功能蛋白聚糖蛋白水解已被确定为关键需求。ADAMTS蛋白酶在许多这些过程中协同表达并发挥作用。除了清除多功能蛋白聚糖外，ADAMTS蛋白酶还产生一种含有N端G1结构域的生物活性多功能蛋白聚糖片段，我们将其命名为多功能激肽。本综述提出这样一种观点，即胚胎细胞外基质不仅进化为胚胎生长和形态发生提供了一个许可环境，而且通过其溶解来影响和调节细胞过程。
