Pancreatic islets of Langerhans display characteristic spatial architecture of their endocrine cell types. This architecture is critical for cell-cell communication and coordinated hormone secretion. Islet architecture is disrupted in type-2 diabetes. Moreover, the generation of architecturally correct islets in vitro remains a challenge in regenerative approaches to type-1 diabetes. Although the characteristic islet architecture is well documented, the mechanisms controlling its formation remain obscure. Here, we report that correct endocrine cell type sorting and the formation of mature islet architecture require the expression of Roundabout (Robo) receptors in β cells. Mice with whole-body deletion of Robo1 and conditional deletion of Robo2 either in all endocrine cells or selectively in β cells show complete loss of endocrine cell type sorting, highlighting the importance of β cells as the primary organizer of islet architecture. Conditional deletion of Robo in mature β cells subsequent to islet formation results in a similar phenotype. Finally, we provide evidence to suggest that the loss of islet architecture in Robo KO mice is not due to β cell transdifferentiation, cell death or loss of β cell differentiation or maturation.

中文翻译：

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朗格汉斯岛的内分泌细胞类型分类和成熟结构需要 β 细胞中 Roundabout 受体的表达。


朗格汉斯胰岛显示出其内分泌细胞类型的特征空间结构。这种结构对于细胞间通讯和协调激素分泌至关重要。 2 型糖尿病的胰岛结构被破坏。此外，在体外生成结构正确的胰岛仍然是 1 型糖尿病再生方法的一个挑战。尽管特征性的胰岛结构已有详细记录，但控制其形成的机制仍然不清楚。在这里，我们报告说，正确的内分泌细胞类型分选和成熟胰岛结构的形成需要β细胞中Roundabout (Robo)受体的表达。在所有内分泌细胞中或选择性地在β细胞中全身删除Robo1并有条件删除Robo2的小鼠表现出内分泌细胞类型分选的完全丧失，凸显了β细胞作为胰岛结构的主要组织者的重要性。在胰岛形成后，在成熟β细胞中条件性删除Robo会导致类似的表型。最后，我们提供的证据表明，Robo KO 小鼠胰岛结构的丧失不是由于 β 细胞转分化、细胞死亡或 β 细胞分化或成熟丧失所致。