Keratin-dependent regulation of protein biosynthesis and cytoskeletal organization during epithelial differentiation

角蛋白属于两个蛋白家族，共有54个成员，从囊胚阶段开始以组织特异性的方式表达。它们为上皮细胞提供机械完整性，是细胞信号蛋白的支架，但是，像其他多基因家族成员一样，单个蛋白的功能尚未得到解决。与许多其他基因家族成员不同，所有角蛋白基因都聚集在小鼠染色体11和15上的两个contigs中，这为解决上述问题提供了一种独特的方法。我们已经开始使用cre/lox系统删除I型和II型角蛋白基因簇，产生真正的角蛋白缺失小鼠，这是进行转基因拯救实验的先决条件。这种经典的基因缺失/基因替换方法有助于理解其他模式生物的发育过程，例如：黑腹果蝇。在该项目的第一阶段，我们关注角蛋白在小鼠胚胎发育中的作用，并询问在缺乏所有其他角蛋白的情况下，单个胚胎或表皮来源的角蛋白对是否支持正常发育。这将揭示表皮角蛋白是否能完成简单上皮角蛋白的结构和信号功能。该研究将对类型特异性角蛋白功能提供重要见解，并对其他大基因家族的组织特异性功能具有普遍意义。

Keratins belong to two protein families with 54 members, expressed from the blastocyst stage onwards in a tissue-specific fashion. The provide mechanical integrity to epithelia and are scaffolds for cell signaling proteins, but, like for other multigene family members, the function of individual proteins has not been resolved. The fact that all keratin genes, unlike members of many other gene families, are clustered in two contigs on chromosomes 11 and 15 in the mouse, offers a unique approach to address the above problem. We have started to use the cre/lox system to delete the type I and type II keratin gene clusters to generate true keratin null mice, a prerequisite for transgenic rescue experiments. This classical approach of gene deletion/gene replacement was instrumental for the understanding of developmental processes in other model organisms, eg. Drosophila melanogaster. In the first phase of this project we focus on the role of keratins in mouse embryonic development and ask whether a single keratin pair of embryonic or epidermal origin supports normal development in the absence of all other keratins. This will reveal whether epidermal keratins can fulfill both structural and signalling functions typical of simple epithelial keratins. The proposed study will provide important insights into type-specific keratin function and is of general significance for tissue-specific functions of other large gene families.