Troy Tammy-Claire, Rahbar Ramtin, Arabzadeh Azadeh, Cheung Robert Man-Kit, Turksen Kursad
Development Program, Ottawa Health Research Institute, 725 Parkdale Ave., Ottawa, Ont., Canada K1Y 4E9.
Mech Dev. 2005 Jun;122(6):805-19. doi: 10.1016/j.mod.2005.03.001. Epub 2005 Apr 21.
Homozygous mice overexpressing Claudin-6 (Cldn6) exhibit a perturbation in the epidermal differentiation program leading to a defective epidermal permeability barrier (EPB) and dehydration induced death ensuing within 48 h of birth [Turksen, K., Troy, T.C., 2002. Permeability barrier dysfunction in transgenic mice overexpressing claudin 6. Development 129, 1775-1784]. Their heterozygous counterparts are also born with an incomplete EPB; however, barrier formation continues after birth and normal hydration levels are achieved by postnatal day 12 allowing survival into adulthood. Heterozygous Inv-Cldn6 mice exhibit a distinct coat phenotype and histological analysis shows mild epidermal hyperkeratosis. Expression of K5 and K14 is aberrant, extending beyond the basal layer into the suprabasal layer where they are not co-localized suggesting that their expression is uncoupled. There is also atypical K17 and patchy K15 expression in the basal layer with no K6 expression in the interfollicular epidermis; together with marked changes in late differentiation markers (e.g. profilaggrin/filaggrin, loricrin, transglutaminase 3) indicating that the normal epidermal differentiation program is modified. The expression compartment of various Cldns is also perturbed although overall protein levels remained comparable. Most notably induction of Cldn5 and Cldn8 was observed in the Inv-Cldn6 epidermis. Heterozygous Inv-Cldn6 animals also exhibit subtle alterations in the differentiation program of the hair follicle including a shorter anagen phase, and altered hair type distribution and length compared to the wild type; the approximately 20% increase in zig-zag hair fibers at the expense of guard hairs and the approximately 30% shorter guard hairs contribute to coat abnormalities in the heterozygous mice. In addition, the transgenic hair follicles exhibit a decreased expression of K15 as well as some hair-specific keratins and express Cldn5 and Cldn18, which are not detectable in the wild type. These data indicate that Cldn6 plays a role in the differentiation processes of the epidermis and hair follicle and supports the notion of a link between Cldn regulation and EPB assembly/maintenance as well as the hair cycle.
过表达Claudin-6（Cldn6）的纯合小鼠在表皮分化程序中表现出紊乱，导致表皮通透性屏障（EPB）缺陷，并在出生后48小时内因脱水而死亡[Turksen, K., Troy, T.C., 2002. 过表达claudin 6的转基因小鼠中的通透性屏障功能障碍。发育129, 1775 - 1784]。它们的杂合子对应物出生时也具有不完全的EPB；然而出生后屏障形成仍在继续，到出生后第12天达到正常水合水平，从而能够存活至成年。杂合Inv-Cldn6小鼠表现出独特的皮毛表型，组织学分析显示轻度表皮角化过度。K5和K14的表达异常，延伸至基底层之外进入棘层，在那里它们不共定位，表明它们的表达解偶联。基底层还有非典型的K17和散在的K15表达，而毛囊间表皮中无K6表达；同时晚期分化标志物（如前丝聚合蛋白/丝聚合蛋白、兜甲蛋白、转谷氨酰胺酶3）有明显变化，表明正常的表皮分化程序被改变。尽管各种Cldn的总体蛋白水平保持相当，但它们的表达区域也受到干扰。最显著的是在Inv-Cldn6表皮中观察到Cldn5和Cldn8的诱导。与野生型相比，杂合Inv-Cldn6动物在毛囊分化程序中也表现出细微变化，包括生长期缩短，毛发类型分布和长度改变；之字形毛纤维增加约20%，以牺牲针毛为代价，且针毛长度缩短约30%，导致杂合小鼠的皮毛出现异常。此外，转基因毛囊中K15以及一些毛发特异性角蛋白的表达降低，并表达野生型中无法检测到的Cldn5和Cldn18。这些数据表明Cldn6在表皮和毛囊的分化过程中起作用，并支持Cldn调节与EPB组装/维持以及毛发周期之间存在联系的观点。
