PDF(Pubmed)
Abstract：
Matricellular proteins comprise several families of secreted proteins that function in higher animals at the interface between cells and their surrounding extracellular matrix. Targeted gene disruptions that result in loss of viability in mice have revealed critical roles for several matricellular proteins in murine embryonic development, including two members of the cellular communication network (CCN) gene family. In contrast, mice lacking single or multiple members of the thrombospondin (THBS) gene family remain viable and fertile. The frequency of loss of function mutants, identified using human deep exome sequencing data, provided evidence that some of the essential genes in mice, including Ccn1, are also essential genes in humans. However, a deficit in loss of function mutants in humans indicated that THBS1 is also highly loss-intolerant. In addition to roles in embryonic development or adult reproduction, genes may be loss-intolerant in humans because their function is needed to survive environmental stresses that are encountered between birth and reproduction. Laboratory mice live in a protected environment that lacks the exposures to pathogens and injury that humans routinely face. However, subjecting Thbs1-/- mice to defined stresses has provided valuable insights into functions of thrombospondin-1 that could account for the loss-intolerance of THBS1 in humans. Stress response models using transgenic mice have identified protective functions of thrombospondin-1 in the cardiovascular system (red) and immune defenses (blue) that could account for its intolerance to loss of function mutants in humans.
摘要：
基质细胞蛋白包括分泌蛋白的几个家族,其在高等动物中在细胞与其周围的细胞外基质之间的界面处发挥作用。导致小鼠生存能力丧失的靶向基因破坏揭示了几种基质细胞蛋白在小鼠胚胎发育中的关键作用。包括细胞通讯网络（CCN）基因家族的两个成员。相比之下,缺乏血小板反应蛋白（THBS）基因家族的单个或多个成员的小鼠仍然可以存活和繁殖。突变体功能丧失的频率，使用人类深层外显子组测序数据鉴定，提供的证据表明小鼠中的一些必需基因，包括Ccn1，也是人类必不可少的基因。然而,人类功能缺失突变体的缺陷表明THBS1也是高度不耐受的。除了在胚胎发育或成人生殖中的作用外，基因在人类中可能是丧失耐受性的，因为它们的功能是在出生和生殖之间遇到的环境压力下生存所必需的。实验室小鼠生活在一个受保护的环境中，缺乏人类常规面临的病原体和伤害。然而,使Thbs1-/-小鼠经受确定的应激为血小板反应蛋白-1的功能提供了有价值的见解，这可以解释人类中THBS1的丢失不耐受。使用转基因小鼠的应激反应模型已经鉴定了血小板反应蛋白-1在心血管系统（红色）和免疫防御（蓝色）中的保护功能，这可能解释了其对人类功能突变体丧失的不耐受性。
