Accelerated re-epithelialization in Dpr2-deficient mice is associated with enhanced response to TGFβ signaling
Accelerated re-epithelialization in Dpr2-deficient mice is associated with enhanced response to TGFβ signaling
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DOI：
10.1242/jcs.032417
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发表时间：
2008-09-01
影响因子：
4
通讯作者：
Meng, Anming
中科院分区：
文献类型：
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作者：
Meng, Fanwei;Cheng, Xuan;Meng, Anming
Dapper（Dpr）/Dact蛋白家族的成员参与不同信号传导途径的调节，包括TGF β/Nodal、经典和非经典Wnt途径。三个Dpr基因，Dpr 1，Dpr 2和Dpr 3，在小鼠胚胎和许多成年组织中表达，然而，它们在体内的功能还没有报道。在这项研究中，我们使用基因敲除方法产生Dpr 2缺陷小鼠。纯合子Dpr 2敲除（Dpr 2（-/-））胚胎发育正常，出生后Dpr 2（-/-）小鼠生长至成年期，没有明显的形态或行为缺陷。我们发现，Dpr 2在表皮角质形成细胞和成年小鼠的毛囊中高度表达，并且Dpr 2缺乏导致皮肤伤口愈合过程中的加速再上皮化。此外，我们证明了Dpr 2功能的丧失增强了角质形成细胞对TGF β刺激的反应，并且TGF β信号通过调节特定整合素基因的表达促进了角质形成细胞与纤连蛋白的粘附和迁移。因此，Dpr 2通过减弱TGF β信号传导在成人皮肤伤口的再上皮化中起抑制作用。
Members of the Dapper (Dpr)/Dact protein family are involved in the regulation of distinct signaling pathways, including TGF beta/Nodal, canonical and noncanonical Wnt pathways. Three Dpr genes, Dpr1, Dpr2 and Dpr3, are expressed in mouse embryos and in many adult tissues; however, their in vivo functions have not been reported. In this study, we generated Dpr2-deficient mice using a gene-knockout approach. Homozygous Dpr2 knockout (Dpr2(-/-)) embryos developed normally and postnatal Dpr2(-/-) mice grew to adulthood without obvious morphological or behavioral defects. We found that Dpr2 was expressed highly in epidermal keratinocytes and in hair follicles of adult mice, and that Dpr2 deficiency resulted in accelerated re-epithelialization during cutaneous wound healing. Furthermore, we demonstrated that loss of Dpr2 function enhanced the responses of keratinocytes to TGF beta stimulation, and that TGF beta signals promoted adhesion to fibronectin and migration of keratinocytes, by regulating the expression of specific integrin genes. Thus, Dpr2 plays an inhibitory role in the re-epithelialization of adult skin wounds by attenuating TGF beta signaling.