Convergence of the insulin and serotonin programs in the pancreatic β-cell.
Convergence of the insulin and serotonin programs in the pancreatic β-cell.
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作者：
Ohta Y;Kosaka Y;Kishimoto N;Wang J;Smith SB;Honig G;Kim H;Gasa RM;Neubauer N;Liou A;Tecott LH;Deneris ES;German MS
尽管胰岛细胞起源于不同的胚层，但它们与神经元，特别是后脑中产生5-羟色胺的神经元有许多共同的发育特征。因此，我们测试了这些发育上的相似之处是否具有功能性后果。我们使用转录图谱、免疫组织化学、DNA结合分析和小鼠遗传模型来评估关键的5-羟色胺能基因在胰腺中的表达和功能。我们发现，胰岛细胞表达编码合成、包装和分泌5-羟色胺所需的所有产物的基因，包括5-羟色胺合成酶色氨酸羟基酶和原型5-羟色胺能转录因子Pet1的两种异构体。与在5-羟色胺能神经元中一样，胰岛中Pet1的表达需要同源结构域转录因子Nkx2.2，而不是Nkx6.1。在β细胞中，Pet1不仅与5-羟色胺能基因结合，而且还与保守的胰岛素基因调控元件结合。缺乏Pet1的小鼠表现出胰岛素产生和分泌减少，糖耐量受损。这些研究表明，一个共同的转录级联驱动β细胞和5-羟色胺能神经元的分化，并赋予它们共同的产生5-羟色胺的能力。这两种细胞类型的相互关联的生物学对于糖尿病的病理和治疗具有重要的意义。
Despite their origins in different germ layers, pancreatic islet cells share many common developmental features with neurons, especially serotonin-producing neurons in the hindbrain. Therefore, we tested whether these developmental parallels have functional consequences. We used transcriptional profiling, immunohistochemistry, DNA-binding analyses, and mouse genetic models to assess the expression and function of key serotonergic genes in the pancreas. We found that islet cells expressed the genes encoding all of the products necessary for synthesizing, packaging, and secreting serotonin, including both isoforms of the serotonin synthetic enzyme tryptophan hydroxylase and the archetypal serotonergic transcription factor Pet1. As in serotonergic neurons, Pet1 expression in islets required homeodomain transcription factor Nkx2.2 but not Nkx6.1. In β-cells, Pet1 bound to the serotonergic genes but also to a conserved insulin gene regulatory element. Mice lacking Pet1 displayed reduced insulin production and secretion and impaired glucose tolerance. These studies demonstrate that a common transcriptional cascade drives the differentiation of β-cells and serotonergic neurons and imparts the shared ability to produce serotonin. The interrelated biology of these two cell types has important implications for the pathology and treatment of diabetes.