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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects
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Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects

机译：QBRICK / Frem1，Fras1和Frem2在基底膜上的相互稳定破坏会引发类似Fraser综合征的缺陷

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摘要

An emerging family of extracellular matrix proteins characterized by 12 consecutive CSPG repeats and the presence of Calx-beta motif(s) includes Fras1, QBRICK/Frem1, and Frem2. Mutations in the genes encoding these proteins have been associated with mouse models of Fraser syndrome, which is characterized by subepidermal blistering, cryptophthalmos, syndactyly, and renal dysmorphogenesis. Here, we report that all of these proteins are localized to the basement membrane, and that their basement membrane localization is simultaneously impaired in Fraser syndrome model mice. In Frem2 mutant mice, not only Frem2 but Fras1 and QBRICK/Frem1 were depleted from the basement membrane zone. This coordinated reduction in basement membrane deposition was also observed in another Fraser syndrome model mouse, in which GRIN, a Fras1- and Frem2-interacting adaptor protein, is primarily affected. Targeted disruption of Qbrick/Frem1 also resulted in diminished expression of Fras1 and Frem2 at the epidermal basement membrane, confirming the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 in this location. When expressed and secreted by transfected cells, these proteins formed a ternary complex, raising the possibility that their reciprocal stabilization at the basement membrane is due to complex formation. Given the close association of Fraser syndrome phenotypes with defective epidermal-dermal interactions, the coordinated assembly of three Fraser syndrome-associated proteins at the basement membrane appears to be instrumental in epidermal-dermal interactions during morphogenetic processes.
机译：一个新兴的细胞外基质蛋白家族，其特征是连续进行12次CSPG重复，并且存在Calx-beta基序，包括Fras1，QBRICK / Frem1和Frem2。编码这些蛋白质的基因中的突变已与Fraser综合征的小鼠模型相关联，该小鼠模型的特征是表皮下水疱，隐眼，综合征和肾畸形。在这里，我们报告所有这些蛋白质都定位于基底膜，并且在Fraser综合征模型小鼠中同时损害了它们的基底膜定位。在Frem2突变小鼠中，不仅Frem2而且Fras1和QBRICK / Frem1从基底膜区被耗尽。在另一只Fraser综合征模型小鼠中也观察到了这种基底膜沉积的协调减少，其中主要影响GRIN（一种与Fras1和Frem2相互作用的衔接蛋白）。 Qbrick / Frem1的靶向破坏也导致表皮基底膜上Fras1和Frem2的表达减少，从而证实了QBRICK / Frem1，Fras1和Frem2在此位置的相互稳定。当被转染的细胞表达和分泌时，这些蛋白质形成三元复合物，从而增加了它们在基底膜上的相互稳定是由于复合物形成的可能性。考虑到弗雷泽综合症表型与不良的表皮-真皮相互作用密切相关，三种与弗雷泽综合症相关的蛋白质在基底膜的协调装配似乎在形态发生过程中对表皮-真皮相互作用起了重要作用。

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