Institut Curie, PSL Research University, CNRS UMR 144, F-75005 Paris, France.
Development. 2024 Nov 1;151(21). doi: 10.1242/dev.203038. Epub 2024 Oct 21.
Intestinal epithelial cells, which are instrumental in nutrient absorption, fluid regulation, and pathogen defense, undergo continuous proliferation and differentiation within the intestinal crypts, migrating towards the luminal surface where they are eventually shed. RAB GTPases are key regulators of intracellular vesicular trafficking and are involved in various cellular processes, including cell migration and polarity. Here, we investigated the role of RAB6 in the development and maintenance of the gut epithelium. We generated conditional knockout mice with RAB6 specifically deleted in the gut epithelium. We found that deletion of the Rab6a gene resulted in embryonic lethality. In adult mice, RAB6 depletion led to altered villus architecture and impaired junction integrity without affecting the segregation of apical and basolateral membrane domains. Further, RAB6 depletion slowed down cell migration and adversely affected both cell proliferation and stem cell maintenance. Notably, the absence of RAB6 resulted in a diminished number of functional stem cells, as evidenced by the rapid death of isolated crypts from Rab6a KO mice when cultured as 3D organoids. Together, these results underscore the essential role of RAB6 in maintaining gut epithelial homeostasis.
肠上皮细胞在营养吸收、液体调节和病原体防御中起着重要作用，它们在肠隐窝中不断增殖和分化，向腔面迁移，最终脱落。RAB GTPases 是细胞内囊泡运输的关键调节因子，参与多种细胞过程，包括细胞迁移和极性。在这里，我们研究了 RAB6 在肠道上皮发育和维持中的作用。我们生成了肠道上皮细胞中特异性缺失 RAB6 的条件性敲除小鼠。我们发现 Rab6a 基因的缺失导致胚胎致死。在成年小鼠中，RAB6 的缺失导致绒毛结构改变和连接完整性受损，而不影响顶侧和基底外侧膜区域的分离。此外，RAB6 的缺失减缓了细胞迁移，并对细胞增殖和干细胞维持产生不利影响。值得注意的是，RAB6 的缺失导致功能性干细胞数量减少，这可以从 Rab6a KO 小鼠分离的隐窝在培养为 3D 类器官时迅速死亡得到证明。总之，这些结果强调了 RAB6 在维持肠道上皮细胞稳态中的重要作用。
