Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1
Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1
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DOI：
10.1242/jcs.03426
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发表时间：
2007-04-15
影响因子：
4
通讯作者：
Haase, Ingo
中科院分区：
文献类型：
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作者：
Tscharntke, Michael;Pofahl, Ruth;Haase, Ingo
为了解决的功能Rac 1角质形成细胞的基底表皮层和毛囊的外根鞘，我们产生的转基因小鼠表达显性抑制突变体的Rac，N17 Rac 1，角蛋白14启动子的控制下。这些小鼠没有表现出明显的皮肤表型，但表现出延长的皮肤伤口上皮再形成。对潜在机制的研究表明，在体内伤口边缘角质形成细胞的增殖和新表皮的向心迁移都受到损害。在表皮特异性缺失Rac 1的小鼠中获得了类似的结果。表达N17 Rac 1转基因的原代表皮角质形成细胞的增殖性低于对照细胞，并且在生长因子刺激后显示ERK 1/2磷酸化降低。粘附，蔓延，随机迁移和关闭的划痕伤口在体外显着抑制胶原蛋白I，并在较小程度上，对纤连蛋白。N17 Rac 1转基因和对照角质形成细胞的细胞动力学频闪分析（SACED）鉴定了与增加的皱褶频率相关的减少的板层突出持续性作为观察到的角质形成细胞粘附和迁移受损的可能机制。我们的结论是，Rac 1是正常的表皮伤口愈合所需的功能，在这种情况下，发挥双重功能，即调节角质形成细胞的增殖和迁移。
To address the functions of Rac1 in keratinocytes of the basal epidermal layer and in the outer root sheath of hair follicles, we generated transgenic mice expressing a dominant inhibitory mutant of Rac, N17Rac1, under the control of the keratin 14 promoter. These mice do not exhibit an overt skin phenotype but show protracted skin wound re-epithelialization. Investigation into the underlying mechanisms revealed that in vivo both proliferation of wound-edge keratinocytes and centripetal migration of the neo-epidermis were impaired. Similar results were obtained in mice with an epidermis-specific deletion of Rac1. Primary epidermal keratinocytes that expressed the N17Rac1 transgene were less proliferative than control cells and showed reduced ERK1/2 phosphorylation upon growth factor stimulation. Adhesion, spreading, random migration and closure of scratch wounds in vitro were significantly inhibited on collagen I and, to a lesser extent, on fibronectin. Stroboscopic analysis of cell dynamics (SACED) of N17Rac1 transgenic and control keratinocytes identified decreased lamella-protrusion persistence in connection with increased ruffle frequency as a probable mechanism for the observed impairment of keratinocyte adhesion and migration. We conclude that Rac1 is functionally required for normal epidermal wound healing and, in this context, exerts a dual function-namely the regulation of keratinocyte proliferation and migration.