Mice Lacking the Extracellular Matrix Protein WARP Develop Normally but Have Compromised Peripheral Nerve Structure and Function
Mice Lacking the Extracellular Matrix Protein WARP Develop Normally but Have Compromised Peripheral Nerve Structure and Function
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DOI：
10.1074/jbc.m806968200
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发表时间：
2009-05-01
影响因子：
4.8
通讯作者：
Bateman, John F.
中科院分区：
文献类型：
--
作者：
Allen, Justin M.;Zamurs, Laura;Bateman, John F.
WARP是最近鉴定的细胞外基质分子，其在永久性软骨和外周神经、肌肉和中枢神经系统脉管系统中的基底膜的不同子集中具有限制性表达。WARP与串珠素相互作用，我们还证明了WARP与VI型胶原蛋白结合，这表明WARP具有桥接结缔组织结构的功能。为了理解WARP的体内功能，我们产生了WARP缺陷型小鼠品系。WARP基因敲除小鼠是健康的、有活力的、能生育的，没有明显的异常。运动功能和行为测试表明，WARP基因敲除小鼠表现出对急性疼痛刺激的显著延迟反应和精细运动协调受损，尽管一般运动功能不受影响，表明外周神经功能受损。WARP相互作用配体的免疫染色表明，胶原VI微纤维基质严重减少，并错误定位在周围神经的WARP无效的小鼠。进一步的超微结构分析显示减少周围神经细胞外基质和异常的部分融合相邻的雪旺细胞基底膜内的纤维状胶原沉积，这表明WARP在稳定胶原间质基质与雪旺细胞基底膜的关联中具有重要功能。相反，其他WARP缺陷的组织，如关节软骨，椎间盘和骨骼肌，没有发现异常，基底膜正常形成。我们的数据表明，虽然WARP不是基底膜形成或肌肉骨骼发育所必需的，但它在周围神经的结构和功能中具有关键作用。
WARP is a recently identified extracellular matrix molecule with restricted expression in permanent cartilages and a distinct subset of basement membranes in peripheral nerves, muscle, and the central nervous system vasculature. WARP interacts with perlecan, and we also demonstrate here that WARP binds type VI collagen, suggesting a function in bridging connective tissue structures. To understand the in vivo function of WARP, we generated a WARP-deficient mouse strain. WARP-null mice were healthy, viable, and fertile with no overt abnormalities. Motor function and behavioral testing demonstrated that WARP-null mice exhibited a significantly delayed response to acute painful stimulus and impaired fine motor coordination, although general motor function was not affected, suggesting compromised peripheral nerve function. Immunostaining of WARP-interacting ligands demonstrated that the collagen VI microfibrillar matrix was severely reduced and mislocalized in peripheral nerves of WARP-null mice. Further ultrastructural analysis revealed reduced fibrillar collagen deposition within the peripheral nerve extracellular matrix and abnormal partial fusing of adjacent Schwann cell basement membranes, suggesting an important function for WARP in stabilizing the association of the collagenous interstitial matrix with the Schwann cell basement membrane. In contrast, other WARP-deficient tissues such as articular cartilage, intervertebral discs, and skeletal muscle showed no detectable abnormalities, and basement membranes formed normally. Our data demonstrate that although WARP is not essential for basement membrane formation or musculoskeletal development, it has critical roles in the structure and function of peripheral nerves.