Growth Retardation, Loss of Desmosomal Adhesion, and Impaired Tight Junction Function Identify a Unique Role of Plakophilin 1 In Vivo
Growth Retardation, Loss of Desmosomal Adhesion, and Impaired Tight Junction Function Identify a Unique Role of Plakophilin 1 In Vivo
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DOI：
10.1016/j.jid.2016.03.021
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发表时间：
2016-07-01
影响因子：
6.5
通讯作者：
Hatzfeld, Mechthild
中科院分区：
文献类型：
--
作者：
Rietscher, Katrin;Wolf, Annika;Hatzfeld, Mechthild
桥粒通过桥粒钙粘蛋白介导强的细胞间粘附，所述桥粒钙粘蛋白与细胞内连接蛋白（包括斑嗜蛋白（PKPs）1-3）相互作用以锚定中间丝。PKP在表皮中表现出重叠但不同的表达模式。到目前为止，个别PKPs在差异调节桥粒功能的贡献还不完全清楚。为了解决PKP 1的作用，我们切除了PKP 1基因。在这里，我们报告说，PKP 1（-/-）小鼠出生在预期的孟德尔比率与出生体重下降，但他们出生后立即出现正常。然而，它们的病情迅速恶化，小鼠在24小时内死亡，在没有明显机械创伤的情况下出现脆弱的皮肤和病变。这是伴随着稀疏和小桥粒。新生的PKP 1（-/-）小鼠表现出紧密连接受损，由内而外屏障受损，而由外而外屏障不受影响。从这些小鼠中分离的角质形成细胞显示出强烈的细胞间凝聚力降低，紧密连接形成延迟，跨上皮阻力降低和增殖率降低。我们的研究显示了PKP 1在桥粒和紧密连接功能中的非冗余和重要作用，并支持PKP 1在生长控制中的作用，这一功能在伤口愈合和表皮癌发生中至关重要。
Desmosomes mediate strong intercellular adhesion through desmosomal cadherins that interact with intracellular linker proteins including plakophilins (PKPs) 1-3 to anchor the intermediate filaments. PKPs show overlapping but distinct expression patterns in the epidermis. So far, the contribution of individual PKPs in differentially regulating desmosome function is incompletely understood. To resolve the role of PKP1 we ablated the PKP1 gene. Here, we report that PKP1(-/-) mice were born at the expected mendelian ratio with reduced birth weight, but they otherwise appeared normal immediately after birth. However, their condition rapidly declined, and the mice died within 24 hours, developing fragile skin with lesions in the absence of obvious mechanical trauma. This was accompanied by sparse and small desmosomes. Newborn PKP1(-/-) mice showed disturbed tight junctions with an impaired inside-out barrier, whereas the outside-in barrier was unaffected. Keratinocytes isolated from these mice showed strongly reduced intercellular cohesion, delayed tight junction formation, and reduced transepithelial resistance and reduced proliferation rates. Our study shows a nonredundant and essential role of PKP1 in desmosome and tight junction function and supports a role of PKP1 in growth control, a function that is crucial in wound healing and epidermal carcinogenesis.