Nkx6.1 and nicx6.2 regulate α- and β-cell formation in zebrafish by acting on pancreatic endocrine progenitor cells
Nkx6.1 and nicx6.2 regulate α- and β-cell formation in zebrafish by acting on pancreatic endocrine progenitor cells
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DOI：
10.1016/j.ydbio.2010.01.025
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发表时间：
2010-04-15
影响因子：
2.7
通讯作者：
Voz, M. L.
中科院分区：
文献类型：
--
作者：
Binot, A. -C.;Manfroid, I.;Voz, M. L.
在小鼠中，Nkx6 基因对于 α 和 β 细胞分化至关重要，但它们调节胰腺亚型规范的分子机制仍然难以捉摸。这里显示，在斑马鱼中，nkx6.1和nkx6.2在早期阶段在第一个胰腺内分泌祖细胞中共表达，但它们的表达域逐渐分离到不同的层中，nkx6.1相对于形成的胰岛在腹侧表达，而nkx6.2主要在β细胞中表达。 nkx6.2 或 nloc6.1 表达的敲低导致 a 细胞几乎完全丧失，但对 β、δ 或 epsilon 细胞没有影响。相比之下，nkx6.1/nkx6.2双重敲低还导致β细胞急剧减少。 nkx6.1和nkx6.2敲低对β和α细胞分化的影响之间的协同作用表明nkx6.1和nkx6.2具有相同的生物活性，α细胞分化所需的总nkx6阈值高于β细胞分化。最后，我们证明 nkx6 作用于胰腺内分泌祖细胞池的建立，其大小与总 nkx6 表达水平相关。根据我们的数据，我们提出了一个模型，其中 nkx6.1 和 nkx6.2 通过建立内分泌祖细胞池来控制 α 和 β 细胞分化。 (C) 2010 Elsevier Inc. 保留所有权利。
In mice, the Nkx6 genes are crucial to alpha- and beta-cell differentiation, but the molecular mechanisms by which they regulate pancreatic subtype specification remain elusive. Here it is shown that in zebrafish, nkx6.1 and nkx6.2 are co-expressed at early stages in the first pancreatic endocrine progenitors, but that their expression domains gradually segregate into different layers, nkx6.1 being expressed ventrally with respect to the forming islet while nkx6.2 is expressed mainly in beta-cells. Knockdown of nkx6.2 or nloc6.1 expression leads to nearly complete loss of a-cells but has no effect on beta-, delta-, or epsilon-cells. In contrast, nkx6.1/nkx6.2 double knockdown leads additionally to a drastic reduction of beta-cells. Synergy between the effects of nkx6.1 and nkx6.2 knockdown on both beta- and alpha-cell differentiation suggests that nkx6.1 and nkx6.2 have the same biological activity, the required total nkx6 threshold being higher for alpha-cell than for beta-cell differentiation. Finally, we demonstrate that the nkx6 act on the establishment of the pancreatic endocrine progenitor pool whose size is correlated with the total nkx6 expression level. On the basis of our data, we propose a model in which nkx6.1 and nkx6.2, by allowing the establishment of the endocrine progenitor pool, control alpha- and beta-cell differentiation. (C) 2010 Elsevier Inc. All rights reserved.