Epidermolysis bullosa and embryonic lethality in mice lacking the multi-PDZ domain protein GRIP1
Epidermolysis bullosa and embryonic lethality in mice lacking the multi-PDZ domain protein GRIP1
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DOI：
10.1073/pnas.092130099
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发表时间：
2002-05-14
影响因子：
11.1
通讯作者：
Pawson, T
中科院分区：
文献类型：
--
作者：
Bladt, F;Tafuri, A;Pawson, T
谷氨酸受体相互作用蛋白1（GRIP 1）是一种由7个PDZ（postsynaptic density-95/Discs large/Escherichoccludens-1）结构域组成的衔接蛋白，能够介导多种蛋白质-蛋白质相互作用。GRIP 1参与神经元突触功能的调节，但其生理作用在体内尚未明确。我们发现，消除小鼠GRIP 1的胚胎致死的结果。GRIP 1（-/-）胚胎发育异常的真皮-表皮连接，导致广泛的皮肤起泡约12天的胚胎生活。水疱（或大疱）的超微结构特征显示致密层下方的真皮-表皮连接处裂开，这一改变使人联想到人类大疱性表皮病的营养不良形式。在侧脑室和覆盖大脑皮质的脑膜中也观察到水泡。这些遗传数据表明GRIP 1支架蛋白是真皮-表皮连接的形成和完整性所必需的，并揭示了PDZ结构域在哺乳动物胚胎发育所必需的超分子结构组织中的重要性。
Glutamate receptor-interacting protein 1 (GRIP1) is an adaptor protein composed of seven PDZ (postsynaptic density-95/Discs large/zona occludens-1) domains, capable of mediating diverse protein-protein interactions. GRIP1 has been implicated in the regulation of neuronal synaptic function, but its physiologic roles hake not been defined in vivo. We find that elimination of murine GRIP1 results in embryonic lethality. GRIP1(-/-) embryos develop abnormalities of the dermo-epidermal junction, resulting in extensive skin blistering around day 12 of embryonic life. Ultra-structural characterization of the blisters (or bullae) revealed cleavage of the dermo-epidermal junction below the lamina densa, an alteration reminiscent of the dystrophic form of human epidermolysis bullosa. Blisters were also observed in the lateral ventricle of the brain and in the meninges covering the cerebral cortex. These genetic data suggest that the GRIP1 scaffolding protein is required for the formation and integrity of the dermo-epidermal junction and reveal the importance of PDZ domains in the organization of supramolecular structures essential for mammalian embryonic development.