应用表皮特异性Cdc42敲除小鼠探讨皮肤发育的信号调控机制

Skin development of mammalian is a complex biological process including proliferation and differenciation of keratinocytes, which play a crucial part in this process. Our research group have done a lot of work on the cell biological functional study of keratinocytes and the role of Rho GTPase family in this, Cdc42 is one of the members of the Rho family. To investigate the function of Cdc42 in skin development,In this subject, to investigate the function of Cdc42 in skin development, we generated mice with a keratinocyte-restricted deletion of Cdc42, which died in 24 hours postnatally, showing Cdc42 maybe have vital function of skin development. In this study, we take K14-specific-Cdc42-knockout mice as animal model to explore the mechanism of small GTPases Cdc42 in skin development: If Cdc42 regulate the migration and differenciation of keratinocytes in skin development? If Cdc42 regulate the migration and differenciation of keratinocytes by MAPK or β-catenin pathways? If MAPK and β-catenin pathways have crosstalk in the process of skin development of mammalian? The answers could give some clues for the mechanism of small GTPase Cdc42 in the process of skin development of mammalian and could lay the foundation for further study of revealing the mechanism of skin diseases.

哺乳动物表皮发育主要包括角质形成细胞增殖与分化等复杂的生物学过程，角质形成细胞的变化是皮肤发育的核心问题。课题组多年来聚焦角质形成细胞生物学功能研究。课题组近期构建了表皮特异性Cdc42基因敲除小鼠，小鼠出生24小时内即死亡，提示：Cdc42信号通路在皮肤发育中发挥重要作用。为进一步探讨Cdc42在皮肤发育中的分子机制，本研究应用表皮特异性Cdc42基因敲除小鼠，集中探讨皮肤发育过程中，Cdc42是否通过调控角质形成细胞增殖和分化而影响皮肤发育？进一步，Cdc42是否通过MAPK通路及β-catenin通路调控角质形成细胞增殖和分化？及MAPK和β-catenin通路在皮肤发育中的相互作用如何？上述问题的解答为阐明小GTP酶Cdc42通路在哺乳动物皮肤发育中机制，为进一步揭示相关皮肤疾病机制打下基础。

哺乳动物表皮发育包括角质形成细胞分化等复杂的生物学过程，角质形成细胞的变化是皮肤发育的核心问题。课题组近期构建了表皮特异性Cdc42 基因敲除小鼠，小鼠出生24 小时内即死亡，提示：Cdc42信号通路在皮肤发育中发挥重要作用。为进一步探讨Cdc42 在皮肤发育中的分子机制，本研究收集不同时期的胚胎标本，从整体水平揭示Cdc42在皮肤角质形成细胞发生发育过程中的作用，发现Cdc42影响表皮角质形成细胞的增殖、分化和细胞连接。值得一提的是，发现Cdc42在表皮屏障形成中发挥至关重要的作用。对E17.5和E19.5（P0）小鼠皮肤进行转录谱测序，聚焦差异基因显著富集的生物功能--角质套膜和角质形成细胞分化，对聚集在该功能的差异基因进行功能验证，发现表皮屏障角质套膜蛋白SPRR1B是Cdc42调节表皮屏障的关键下游分子。Cdc42-SPRR1B在表皮屏障形成过程中协调发挥重要作用。阐明小GTP 酶Cdc42 通路在哺乳动物皮肤发育和表皮屏障的调控机制，为进一步揭示相关皮肤疾病机制打下基础。