Endocrine cells of the zebrafish digestive system play an important role in regulating metabolism and include pancreatic endocrine cells (PECs) clustered in the islets of Langerhans and the enteroendocrine cells (EECs) scattered in the intestinal epithelium. Despite EECs and PECs are being located in distinct organs, their differentiation involves shared molecular mechanisms and transcription factors. However, their degree of relatedness remains unexplored. In this study, we investigated comprehensively the similarity of EECs and PECs by defining their transcriptomic landscape and comparing the regulatory programmes controlled by Pax6b, a key player in both EEC and PEC differentiations. RNA sequencing was performed on EECs and PECs isolated from wild-type and pax6b mutant zebrafish. Data mining of wild-type zebrafish EEC data confirmed the expression of orthologues for most known mammalian EEC hormones, but also revealed the expression of three additional neuropeptide hormones (Proenkephalin-a, Calcitonin-a and Adcyap1a) not previously reported to be expressed by EECs in any species. Comparison of transcriptomes from EECs, PECs and other zebrafish tissues highlights a very close similarity between EECs and PECs, with more than 70% of genes being expressed in both endocrine cell types. Comparison of Pax6b-regulated genes in EECs and PECs revealed a significant overlap. pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. Finally, we show that the homeodomain of Pax6b is dispensable for its action in both EECs and PECs. We have analysed the transcriptomic landscape of wild-type and pax6b mutant zebrafish EECs and PECs. Our study highlights the close relatedness of EECs and PECs at the transcriptomic and regulatory levels, supporting the hypothesis of a common phylogenetic origin and underscoring the potential implication of EECs in metabolic diseases such as type 2 diabetes.

中文翻译：

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斑马鱼的胰腺和肠道内分泌细胞具有共同的转录组特征和调控程序。

斑马鱼消化系统的内分泌细胞在调节新陈代谢中起重要作用，其中包括胰岛内分泌细胞（PEC）聚集在朗格汉斯胰岛和肠内分泌细胞（EECs）分散在肠上皮中。尽管EEC和PEC位于不同的器官中，但它们的分化涉及共享的分子机制和转录因子。但是，它们的相关程度仍未开发。在这项研究中，我们通过定义EEC和PEC的转录组图谱并比较Pax6b（EEC和PEC差异化的关键参与者）控制的调控程序，全面研究了EEC和PEC的相似性。对从野生型和pax6b突变斑马鱼分离的EEC和PEC进行RNA测序。对野生型斑马鱼EEC数据的数据挖掘证实了大多数已知的哺乳动物EEC激素的直向同源物的表达，但还揭示了以前没有由EEC报道的三种其他神经肽激素（前脑啡肽-a，降钙素-a和Adcyap1a）的表达。在任何物种中。来自EEC，PEC和其他斑马鱼组织的转录组的比较突出显示了EEC和PEC之间的非常相似，其中超过70％的基因在两种内分泌细胞类型中表达。在EECs和PECs中Pax6b调控基因的比较显示出明显的重叠。pax6b功能丧失不会影响EEC和PEC的总数，而是会破坏内分泌细胞亚型之间的平衡，导致肠道和胰脏中表达生长素释放肽和胃动素样细胞的增加，而其他胰腺内分泌细胞（如胰脏中的β和δ细胞以及肠中的pyyb表达细胞）却以这种形式为代价。最后，我们表明Pax6b的同源域对于在EEC和PEC中的作用都是必不可少的。我们已经分析了野生型和pax6b突变斑马鱼EEC和PECs的转录组景观。我们的研究突出了EEC和PEC在转录组和调节水平上的紧密相关性，支持了常见系统发生起源的假说，并强调了EEC在2型糖尿病等代谢性疾病中的潜在意义。我们表明Pax6b的同源域是其在EEC和PEC中的作用所必需的。我们已经分析了野生型和pax6b突变斑马鱼EEC和PECs的转录组景观。我们的研究突出了EEC和PEC在转录组和调节水平上的紧密相关性，支持了常见系统发生起源的假说，并强调了EEC在2型糖尿病等代谢性疾病中的潜在意义。我们表明，Pax6b的同源域对于在EEC和PEC中的作用是必不可少的。我们已经分析了野生型和pax6b突变斑马鱼EEC和PECs的转录组景观。我们的研究突出了EEC和PEC在转录组和调节水平上的密切相关性，支持了常见系统发生起源的假说，并强调了EEC在2型糖尿病等代谢性疾病中的潜在意义。