Tissue Array Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-8322, USA.
Endocrinology. 2010 Aug;151(8):4024-30. doi: 10.1210/en.2009-1251. Epub 2010 Jun 16.
The pancreatic alpha- and beta-cells are critical components in regulating blood glucose homeostasis via secretion of glucagon and insulin, respectively. Both cell types are typically localized in the islets of Langerhans. However, little is known about the roles of paracrine interactions that contribute to their physiological functions. The lack of suitable cell lines to study alpha- and beta-cells interactions have led us to develop an alpha-cell-specific Cre-expressing transgenic line utilizing a glucagon promoter sequence, the Glu-Cre transgenic mouse. Here, we demonstrate that the Glu-Cre could specifically and efficiently excise floxed target genes in adult islet alpha-cells. We further showed that deletion of the tumor suppressor gene, multiple endocrine neoplasia type 1 (Men1), in alpha-cells led to tumorigenesis. However, to our surprise, the lack of Men1 in alpha-cells did not result in glucagonomas but rather beta-cell insulinomas. Because deletion of the Men1 alleles was only present in alpha-cells, our data suggested that cross communication between alpha- and beta-cells contributes to tumorigenesis in the absence of Men1. Together, we believed that the new model systems described here will allow future studies to decipher cellular interactions between islet alpha- and beta-cells in a physiological context.
胰岛的α细胞和β细胞分别通过分泌胰高血糖素和胰岛素来调节血糖稳态，是至关重要的组成部分。这两种细胞类型通常位于胰岛中。然而，关于促进其生理功能的旁分泌相互作用的作用知之甚少。缺乏合适的细胞系来研究α细胞和β细胞的相互作用，促使我们利用胰高血糖素启动子序列开发了一种α细胞特异性表达 Cre 的转基因系，即 Glu-Cre 转基因小鼠。在这里，我们证明了 Glu-Cre 可在成年胰岛α细胞中特异性且有效地切除 floxed 靶基因。我们进一步表明，肿瘤抑制基因多发性内分泌肿瘤 1（Men1）在α细胞中的缺失会导致肿瘤发生。然而，令我们惊讶的是，α细胞中缺乏 Men1 并不会导致胰高血糖素瘤，而是β细胞胰岛素瘤。由于 Men1 等位基因的缺失仅存在于α细胞中，我们的数据表明，在缺乏 Men1 的情况下，α细胞和β细胞之间的交叉通讯有助于肿瘤发生。总之，我们相信这里描述的新模型系统将允许未来的研究在生理环境下阐明胰岛α细胞和β细胞之间的细胞相互作用。
