Collombat Patrick, Xu Xiaobo, Ravassard Philippe, Sosa-Pineda Beatriz, Dussaud Sébastien, Billestrup Nils, Madsen Ole D, Serup Palle, Heimberg Harry, Mansouri Ahmed
Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg, D-37077 Göttingen, Germany.
Cell. 2009 Aug 7;138(3):449-62. doi: 10.1016/j.cell.2009.05.035.
We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature alpha cells, to adopt a beta cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon+ cell neogenesis requiring the re-expression of the proendocrine gene Ngn3. However, the newly formed alpha cells fail to correct the hypoglucagonemia since they subsequently acquire a beta cell phenotype upon Pax4 ectopic expression. Notably, this cycle of neogenesis and redifferentiation caused by ectopic expression of Pax4 in alpha cells is capable of restoring a functional beta cell mass and curing diabetes in animals that have been chemically depleted of beta cells.
我们之前曾报道，Arx和/或Pax4基因活性的丧失会导致小鼠胰腺中不同内分泌细胞亚型的命运发生转变，但不影响内分泌细胞的总数。在此，我们使用不同的细胞特异性启动子条件性地异位表达Pax4，并证明Pax4促使内分泌前体细胞以及成熟的α细胞转变为β细胞命运。这导致胰高血糖素缺乏，引发代偿性且持续的胰高血糖素阳性细胞新生，这需要内分泌前体基因Ngn3的重新表达。然而，新形成的α细胞无法纠正低胰高血糖素血症，因为它们随后在Pax4异位表达时获得了β细胞表型。值得注意的是，α细胞中Pax4异位表达所引起的这种新生和再分化循环能够恢复功能性β细胞群，并治愈化学方法去除β细胞的动物的糖尿病。
