Excess biglycan causes eyelid malformation by perturbing muscle development and TGF-α signaling
Excess biglycan causes eyelid malformation by perturbing muscle development and TGF-α signaling
复制标题
DOI：
10.1016/j.ydbio.2004.09.022
复制
发表时间：
2005-01-01
影响因子：
2.7
通讯作者：
Kao, WWY
中科院分区：
文献类型：
--
作者：
Hayashi, Y;Liu, CY;Kao, WWY
发育期间的组织形态发生受生长因子和细胞因子调节，并且其特征在于响应于信号传导分子（例如，生长因子、细胞因子等）的细胞外基质（ECM）的不断重塑。结合生长因子的蛋白聚糖是胚胎发育期间组织形态发生的潜在调节剂。在这项研究中，我们发现，在角膜蛋白聚糖启动子下过度表达双糖蛋白聚糖的转基因小鼠表现出暴露性角膜炎和过早睁眼，这是由于眼睑肌肉形成的扰动和睑板腺形成的失败造成的非感染性眼睑溃疡。此外，体外分析显示双糖链蛋白聚糖与TGF-α结合，从而中断眼睑上皮诱导的间充质细胞迁移所必需的EGFR信号传导途径。过量双糖链聚糖导致的TGF-α信号传导缺陷通过TGF-α引起的HB-EGF表达的EGFR信号传导途径的自分泌或旁分泌环的中断而进一步增强。这些结果与以下概念一致：在生理条件下，由间充质细胞分泌的双糖蛋白聚糖充当用于形成TGF-α梯度的调节分子，所述TGF-α梯度充当眼睑形态发生的形态原。(C)2004年爱思唯尔公司All rights reserved.
Tissue morphogenesis during development is regulated by growth factors and cytokines, and is characterized by constant remodeling of extracellular matrix (ECM) in response to signaling molecules, for example, growth factors, cytokines, and so forth. Proteoglycans that bind growth factors are potential regulators of tissue morphogenesis during embryonic development. In this study, we showed that transgenic mice overexpressing biglycan under the keratocan promoter exhibited exposure keratitis and premature eye opening from noninfectious eyelid ulceration due to perturbation of eyelid muscle formation and the failure of meibomian gland formation. In addition, in vitro analysis revealed that biglycan binds to TGF-alpha, thus interrupting EGFR signaling pathways essential for mesenchymal cell migration induced by eyelid epithelium. The defects of TGF-alpha signaling by excess biglycan were further augmented by the interruption of the autocrine or paracrine loop of the EGFR signaling pathway of HB-EGF expression elicited by TGF-alpha. These results are consistent with the notion that under physiological conditions, biglycan secreted by mesenchymal cells serves as a regulatory molecule for the formation of a TGF-alpha gradient serving as a morphogen of eyelid morphogenesis. (C) 2004 Elsevier Inc. All rights reserved.