肠道硝酸神经元密度的个体间差异受 GDNF 水平和 ETV1 的调节。

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2024-01-01 DOI:10.1016/j.jcmgh.2024.101405

Heikki T. Virtanen , Peyman Choopanian , L. Lauriina Porokuokka , Richard Forsgård , Daniel R. Garton , Soophie Olfat , Riitta Korpela , Mehdi Mirzaie , Jaan-Olle Andressoo

{"title":"肠道硝酸神经元密度的个体间差异受 GDNF 水平和 ETV1 的调节。","authors":"Heikki T. Virtanen , Peyman Choopanian , L. Lauriina Porokuokka , Richard Forsgård , Daniel R. Garton , Soophie Olfat , Riitta Korpela , Mehdi Mirzaie , Jaan-Olle Andressoo","doi":"10.1016/j.jcmgh.2024.101405","DOIUrl":null,"url":null,"abstract":"<div><h3>Background & Aims</h3><div>The size and function of the enteric nervous system (ENS) can vary substantially between individuals. Because ENS function is involved in the etiology of a growing number of common human diseases, understanding mechanisms that regulate ENS variation is important.</div></div><div><h3>Methods</h3><div>We analyzed RNAseq data from 41 normal adult human colon biopsies and single-cell RNA-seq data from human and mouse developing gut. To establish cause-consequence relationship we used alleles in mice that allow levels change of the candidate effector molecule in the comparable range to human samples. We used siRNA and primary neuronal cultures to define downstream molecular events and characterized gut functional changes in mice where molecular phenotypes paralleled findings in humans.</div></div><div><h3>Results</h3><div>We found that glial cell line–derived neurotrophic factor (GDNF) levels in the human colon vary about 5-fold and correlate strongly with nitrergic marker expression. In mice, we defined that GDNF levels are regulated via its 3’ untranslated region (3’ UTR) in the gastrointestinal tract and observed similar correlation between GDNF levels and nitrergic lineage development. We identified miR-9 and miR-133 as evolutionarily conserved candidates for negative regulation of GDNF expression in the gastrointestinal tract. Functionally, an increase in inhibitory nitrergic innervation results in an increase in gastrointestinal tract transit time, stool size, and water content accompanied with modestly reduced epithelial barrier function. Mechanistically, we found that GDNF levels regulate nitrergic lineage development via induction of transcription factor ETV1, corroborated by single-cell gene expression data in human and mouse developing enteric neurons.</div></div><div><h3>Conclusions</h3><div>Our results reveal how normal variation in GDNF levels influence ENS size, composition, and gut function, suggesting a mechanism for well-known interindividual variation among those parameters.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 6","pages":"Article 101405"},"PeriodicalIF":7.1000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Interindividual Variation in Gut Nitrergic Neuron Density Is Regulated By GDNF Levels and ETV1\",\"authors\":\"Heikki T. Virtanen , Peyman Choopanian , L. Lauriina Porokuokka , Richard Forsgård , Daniel R. Garton , Soophie Olfat , Riitta Korpela , Mehdi Mirzaie , Jaan-Olle Andressoo\",\"doi\":\"10.1016/j.jcmgh.2024.101405\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background & Aims</h3><div>The size and function of the enteric nervous system (ENS) can vary substantially between individuals. Because ENS function is involved in the etiology of a growing number of common human diseases, understanding mechanisms that regulate ENS variation is important.</div></div><div><h3>Methods</h3><div>We analyzed RNAseq data from 41 normal adult human colon biopsies and single-cell RNA-seq data from human and mouse developing gut. To establish cause-consequence relationship we used alleles in mice that allow levels change of the candidate effector molecule in the comparable range to human samples. We used siRNA and primary neuronal cultures to define downstream molecular events and characterized gut functional changes in mice where molecular phenotypes paralleled findings in humans.</div></div><div><h3>Results</h3><div>We found that glial cell line–derived neurotrophic factor (GDNF) levels in the human colon vary about 5-fold and correlate strongly with nitrergic marker expression. In mice, we defined that GDNF levels are regulated via its 3’ untranslated region (3’ UTR) in the gastrointestinal tract and observed similar correlation between GDNF levels and nitrergic lineage development. We identified miR-9 and miR-133 as evolutionarily conserved candidates for negative regulation of GDNF expression in the gastrointestinal tract. Functionally, an increase in inhibitory nitrergic innervation results in an increase in gastrointestinal tract transit time, stool size, and water content accompanied with modestly reduced epithelial barrier function. Mechanistically, we found that GDNF levels regulate nitrergic lineage development via induction of transcription factor ETV1, corroborated by single-cell gene expression data in human and mouse developing enteric neurons.</div></div><div><h3>Conclusions</h3><div>Our results reveal how normal variation in GDNF levels influence ENS size, composition, and gut function, suggesting a mechanism for well-known interindividual variation among those parameters.</div></div>\",\"PeriodicalId\":55974,\"journal\":{\"name\":\"Cellular and Molecular Gastroenterology and Hepatology\",\"volume\":\"18 6\",\"pages\":\"Article 101405\"},\"PeriodicalIF\":7.1000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cellular and Molecular Gastroenterology and Hepatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2352345X24001607\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular and Molecular Gastroenterology and Hepatology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2352345X24001607","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

背景与目的：不同个体的肠道神经系统（ENS）的大小和功能会有很大差异。由于 ENS 功能与越来越多的人类常见疾病的病因有关，因此了解调控 ENS 变异的机制非常重要：我们分析了来自 41 例正常成人结肠活检组织的 RNAseq 数据，以及来自人类和小鼠发育中肠道的单细胞 RNAseq 数据。为了确定因果关系，我们利用了小鼠的等位基因，这些等位基因允许候选效应分子的水平在与人类样本相当的范围内发生变化。我们利用 siRNA 和原代神经元培养来确定下游分子事件，并描述了小鼠肠道功能变化的特征，其中的分子表型与人类的研究结果一致：结果：我们发现，人类结肠中的 GDNF 水平变化约为 5 倍，并且与硝酸神经元标记表达密切相关。在小鼠中，我们确定 GDNF 水平是通过其在消化道中的 3' 非翻译区（3' UTR）调节的，并观察到 GDNF 水平与能硝细胞系发育之间存在类似的相关性。我们发现，miR-9 和 miR-133 是消化道中负性调控 GDNF 表达的进化保守候选基因。在功能上，抑制性硝酸神经支配的增加会导致消化道转运时间、粪便体积和含水量的增加，同时上皮屏障功能也会适度降低。从机理上讲，我们发现 GDNF 水平通过诱导转录因子 ETV1 来调节硝能神经细胞系的发育，人和小鼠发育中的肠神经元的单细胞基因表达数据证实了这一点：我们的研究结果揭示了 GDNF 水平的正常变化如何影响 ENS 的大小、组成和肠道功能，并为这些参数之间众所周知的个体差异提出了一种机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Interindividual Variation in Gut Nitrergic Neuron Density Is Regulated By GDNF Levels and ETV1

Background & Aims

The size and function of the enteric nervous system (ENS) can vary substantially between individuals. Because ENS function is involved in the etiology of a growing number of common human diseases, understanding mechanisms that regulate ENS variation is important.

Methods

We analyzed RNAseq data from 41 normal adult human colon biopsies and single-cell RNA-seq data from human and mouse developing gut. To establish cause-consequence relationship we used alleles in mice that allow levels change of the candidate effector molecule in the comparable range to human samples. We used siRNA and primary neuronal cultures to define downstream molecular events and characterized gut functional changes in mice where molecular phenotypes paralleled findings in humans.

Results

We found that glial cell line–derived neurotrophic factor (GDNF) levels in the human colon vary about 5-fold and correlate strongly with nitrergic marker expression. In mice, we defined that GDNF levels are regulated via its 3’ untranslated region (3’ UTR) in the gastrointestinal tract and observed similar correlation between GDNF levels and nitrergic lineage development. We identified miR-9 and miR-133 as evolutionarily conserved candidates for negative regulation of GDNF expression in the gastrointestinal tract. Functionally, an increase in inhibitory nitrergic innervation results in an increase in gastrointestinal tract transit time, stool size, and water content accompanied with modestly reduced epithelial barrier function. Mechanistically, we found that GDNF levels regulate nitrergic lineage development via induction of transcription factor ETV1, corroborated by single-cell gene expression data in human and mouse developing enteric neurons.

Conclusions

Our results reveal how normal variation in GDNF levels influence ENS size, composition, and gut function, suggesting a mechanism for well-known interindividual variation among those parameters.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.