Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression.
Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression.
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DOI：
10.1016/j.ydbio.2011.08.001
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发表时间：
2011-11-01
影响因子：
2.7
通讯作者：
Sussel L
中科院分区：
文献类型：
--
作者：
Mastracci TL;Wilcox CL;Arnes L;Panea C;Golden JA;May CL;Sussel L
Nkx2.2 和 Arx 是重要的胰腺转录因子。 Nkx2.2 对于胰岛 α、β、PP 和 epsilon 细胞谱系的适当规范是必需的，而 Arx 是形成 α、β、δ 和 PP 细胞的正确比例所必需的。为了开始了解 Nkx2.2 和 Arx 在内分泌细胞谱系发育中的协同功能，我们在 Nkx2.2 无效背景上生成了祖细胞特异性的 Arx 缺失。对这些突变体的分析表明，Nkx2.2 无效胰腺中 ghrelin 细胞群的扩增不依赖于 Arx；然而，Arx 对于 Nkx2.2 突变 epsilon 细胞中 ghrelin mRNA 水平的上调是必需的。或者，在缺乏 Arx 的情况下，δ 细胞数量增加，Nkx2.2 成为抑制生长抑素基因表达所必需的。有趣的是，Nkx2.2/Arx复合突变体（Nkx2.2null；ArxΔpanc）中生长素释放肽和生长抑素表达的失调导致生长素释放肽+/生长抑素+共表达细胞的出现。这些复合突变体还揭示了 Nkx2.2 和 Arx 在 PP 细胞谱系调节中的遗传相互作用；当 Nkx2.2 被删除时，PP 细胞数量减少，但在 Nkx2.2null;ArxΔpanc 突变体中恢复到野生型数量。此外，在特定胰腺细胞群中条件性删除 Arx 证实 Arx 的功能在 Neurog3+ 内分泌祖细胞中是必需的。这些实验共同确定了内分泌祖细胞内 Nkx2.2 和 Arx 之间的新型遗传相互作用，确保内分泌激素产生细胞的正确规范和调节。
Nkx2.2 and Arx are essential pancreatic transcription factors. Nkx2.2 is necessary for the appropriate specification of the islet alpha, beta, PP and epsilon cell lineages, whereas Arx is required to form the correct ratio of alpha, beta, delta and PP cells. To begin to understand the cooperative functions of Nkx2.2 and Arx in the development of endocrine cell lineages, we generated progenitor cell-specific deletions of Arx on the Nkx2.2 null background. The analysis of these mutants demonstrates that expansion of the ghrelin cell population in the Nkx2.2 null pancreas is not dependent on Arx; however, Arx is necessary for the upregulation of ghrelin mRNA levels in Nkx2.2 mutant epsilon cells. Alternatively, in the absence of Arx, delta cell numbers are increased and Nkx2.2 becomes essential for the repression of somatostatin gene expression. Interestingly, the dysregulation of ghrelin and somatostatin expression in the Nkx2.2/Arx compound mutant (Nkx2.2null;ArxΔpanc) results in the appearance of ghrelin+/somatostatin+ co-expressing cells. These compound mutants also revealed a genetic interaction between Nkx2.2 and Arx in the regulation of the PP cell lineage; the PP cell population is reduced when Nkx2.2 is deleted but is restored back to wildtype numbers in the Nkx2.2null;ArxΔpanc mutant. Moreover, conditional deletion of Arx in specific pancreatic cell populations established that the functions of Arx are necessary in the Neurog3+ endocrine progenitors. Together, these experiments identify novel genetic interactions between Nkx2.2 and Arx within the endocrine progenitor cells that ensure the correct specification and regulation of endocrine hormone-producing cells.
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