Gene- and tissue-level interactions in normal gastrointestinal development and Hirschsprung disease
Gene- and tissue-level interactions in normal gastrointestinal development and Hirschsprung disease
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DOI：
10.1073/pnas.1908756116
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发表时间：
2019-12-26
影响因子：
11.1
通讯作者：
Chakravarti, Aravinda
中科院分区：
文献类型：
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作者：
Chatterjee, Sumantra;Nandakumar, Priyanka;Chakravarti, Aravinda
在小鼠胚胎期E10.5-E14.5，肠道从内胚层组织发育为具有多种不同结构和功能的器官需要很长时间。在此过程中，一个主要事件是肠神经嵴细胞（ENCC）对肠道的神经支配，以建立肠神经系统（ENS）。为了了解肠道和ENS发育的分子过程，我们在E10.5，E12.5和E14.5从两种性别的野生型小鼠肠道中生成RNA测序谱。我们还从纯合子Ret无效胚胎（一种先天性巨结肠病（HSCR）模型，其中ENS缺失）中生成了这些图谱。这些数据揭示了4个主要特征：1）在E10.5-E14.5之间，发育遗传程序由主要转录因子及其修饰物的表达转变为控制组织的基因（2）Ret的主要作用不仅是促进ENCC向肠神经元分化，而且还影响肠间充质和上皮细胞; 3）肌肉遗传程序对ENS发育产生显著影响; 4）肠道发育概况的性别差异很小。所确定的遗传程序及其在发育过程中的变化表明，细胞自主和非自主因素以及不同发育肠道组织之间的相互作用对正常ENS发育及其疾病都很重要。
The development of the gut from endodermal tissue to an organ with multiple distinct structures and functions occurs over a prolonged time during embryonic days E10.5-E14.5 in the mouse. During this process, one major event is innervation of the gut by enteric neural crest cells (ENCCs) to establish the enteric nervous system (ENS). To understand the molecular processes underpinning gut and ENS development, we generated RNA-sequencing profiles from wild-type mouse guts at E10.5, E12.5, and E14.5 from both sexes. We also generated these profiles from homozygous Ret null embryos, a model for Hirschsprung disease (HSCR), in which the ENS is absent. These data reveal 4 major features: 1) between E10.5 and E14.5 the developmental genetic programs change from expression of major transcription factors and its modifiers to genes controlling tissue (epithelium, muscle, endothelium) specialization; 2) the major effect of Ret is not only on ENCC differentiation to enteric neurons but also on the enteric mesenchyme and epithelium; 3) a muscle genetic program exerts significant effects on ENS development; and 4) sex differences in gut development profiles are minor. The genetic programs identified, and their changes across development, suggest that both cell autonomous and nonautonomous factors, and interactions between the different developing gut tissues, are important for normal ENS development and its disorders.