Kordowich Simon, Collombat Patrick, Mansouri Ahmed, Serup Palle
Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany.
BMC Dev Biol. 2011 Aug 31;11:52. doi: 10.1186/1471-213X-11-52.
Nkx2.2 and Arx represent key transcription factors implicated in the specification of islet cell subtypes during pancreas development. Mice deficient for Arx do not develop any alpha-cells whereas beta- and delta-cells are found in considerably higher numbers. In Nkx2.2 mutant animals, alpha- and beta-cell development is severely impaired whereas a ghrelin-expressing cell population is found augmented.Notably, Arx transcription is clearly enhanced in Nkx2.2-deficient pancreata. Hence in order to precise the functional link between both factors we performed a comparative analysis of Nkx2.2/Arx single- and double-mutants but also of Pax6-deficient animals.
We show that most of the ghrelin+ cells emerging in pancreata of Nkx2.2- and Pax6-deficient mice, express the alpha-cell specifier Arx, but also additional beta-cell related genes. In Nkx2.2-deficient mice, Arx directly co-localizes with iAPP, PC1/3 and Pdx1 suggesting an Nkx2.2-dependent control of Arx in committed beta-cells. The combined loss of Nkx2.2 and Arx likewise results in the formation of a hyperplastic ghrelin+ cell population at the expense of mature alpha- and beta-cells. Surprisingly, such Nkx2.2-/-Arx- ghrelin+ cells also express the somatostatin hormone.
Our data indicate that Nkx2.2 acts by reinforcing the transcriptional networks initiated by Pax4 and Arx in early committed beta- and alpha-cell, respectively. Our analysis also suggests that one of the coupled functions of Nkx2.2 and Pax4 is to counteract Arx gene activity in early committed beta-cells.
Nkx2.2和Arx是胰腺发育过程中涉及胰岛细胞亚型特化的关键转录因子。Arx基因缺失的小鼠不会发育出任何α细胞，而β细胞和δ细胞的数量则显著增加。在Nkx2.2突变动物中，α细胞和β细胞的发育严重受损，而表达胃饥饿素的细胞群体数量增加。值得注意的是，在Nkx2.2基因缺失的胰腺中，Arx转录明显增强。因此，为了明确这两种因子之间的功能联系，我们对Nkx2.2/Arx单突变和双突变小鼠以及Pax6基因缺失的动物进行了比较分析。
我们发现，在Nkx2.2和Pax6基因缺失的小鼠胰腺中出现的大多数胃饥饿素阳性细胞，既表达α细胞特异性因子Arx，也表达其他与β细胞相关的基因。在Nkx2.2基因缺失的小鼠中，Arx直接与胰岛淀粉样多肽、PC1/3和Pdx1共定位，表明在已分化的β细胞中，Arx受Nkx2.2依赖性调控。Nkx2.2和Arx的共同缺失同样导致以成熟α细胞和β细胞为代价形成增生性胃饥饿素阳性细胞群体。令人惊讶的是，这种Nkx2.2 - / - Arx - 胃饥饿素阳性细胞也表达生长抑素。
我们的数据表明，Nkx2.2分别通过加强Pax4和Arx在早期已分化的β细胞和α细胞中启动的转录网络发挥作用。我们的分析还表明，Nkx2.2和Pax4的耦合功能之一是在早期已分化的β细胞中抵消Arx基因的活性。
