Rac1 regulates pancreatic islet morphogenesis
Rac1 regulates pancreatic islet morphogenesis
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DOI：
10.1186/1471-213x-9-2
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发表时间：
2009-01-06
影响因子：
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通讯作者：
Semb, Henrik
中科院分区：
文献类型：
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作者：
Greiner, Thomas U.;Kesavan, Gokul;Semb, Henrik
背景：胰岛起源于胰腺导管上皮内的内分泌祖细胞。伴随着这些祖细胞分化成产生细胞的细胞，这些细胞分层、聚集并从导管上皮迁移离开。调节胰岛细胞分层和细胞迁移的细胞和分子机制知之甚少。广泛的生化和细胞生物学研究，使用培养的细胞表明，Rac 1，小GTPases的Rho家族的成员，作为一个关键的调节细胞migration.Results：要解决的功能作用的Rac 1在胰岛形态发生，我们产生的转基因小鼠表达显性负Rac 1的调节下的大鼠胰岛素启动子。阻断β细胞中的Rac 1功能可抑制其在体内从导管上皮迁移。因此，转基因胰岛细胞在体外的铺展受到影响。我们还表明，EGF受体配体β细胞素诱导肌动蛋白重塑和细胞扩散在野生型胰岛，但不是在转基因胰岛。最后，我们证明细胞与细胞接触E-钙粘蛋白因阻断Rac 1活性而增加。结论：我们的数据支持Rac 1信号通过调节E-钙粘蛋白介导的细胞与细胞粘附来控制胰岛细胞迁移的模型。此外，在体外实验表明，β细胞素刺激胰岛细胞的扩展和肌动蛋白重塑是妥协的转基因胰岛，这表明β细胞素可能作为一个调节器的Rac 1活性和胰岛迁移在体内。我们的研究结果进一步强调了Rac 1作为组织和器官形态发生过程中细胞迁移和细胞粘附的关键调节因子。
Background: Pancreatic islets of Langerhans originate from endocrine progenitors within the pancreatic ductal epithelium. Concomitant with differentiation of these progenitors into hormone-producing cells such cells delaminate, aggregate and migrate away from the ductal epithelium. The cellular and molecular mechanisms regulating islet cell delamination and cell migration are poorly understood. Extensive biochemical and cell biological studies using cultured cells demonstrated that Rac1, a member of the Rho family of small GTPases, acts as a key regulator of cell migration.Results: To address the functional role of Rac1 in islet morphogenesis, we generated transgenic mice expressing dominant negative Rac1 under regulation of the Rat Insulin Promoter. Blocking Rac1 function in beta cells inhibited their migration away from the ductal epithelium in vivo. Consistently, transgenic islet cell spreading was compromised in vitro. We also show that the EGF-receptor ligand betacellulin induced actin remodelling and cell spreading in wild-type islets, but not in transgenic islets. Finally, we demonstrate that cell-cell contact E-cadherin increased as a consequence of blocking Rac1 activity.Conclusion: Our data support a model where Rac1 signalling controls islet cell migration by modulating E-cadherin-mediated cell-cell adhesion. Furthermore, in vitro experiments show that betacellulin stimulated islet cell spreading and actin remodelling is compromised in transgenic islets, suggesting that betacellulin may act as a regulator of Rac1 activity and islet migration in vivo. Our results further emphasize Rac1 as a key regulator of cell migration and cell adhesion during tissue and organ morphogenesis.