EMB is essential for enteric nervous system development mediated by PI3K signaling.

IF 10.4 1区生物学 Q1 GENETICS & HEREDITY

Genome Medicine Pub Date : 2025-09-25 DOI:10.1186/s13073-025-01538-1

Zhi Li, Didi Zhuansun, Xinyao Meng, Heying Yang, Jun Xiao, Yingjian Chen, Jing Wang, Xiaosi Yu, Zejian Li, Jingyi You, Xuyong Chen, Chenzhao Feng, Luyao Wu, Xufeng Chu, Weicheng Duan, Kang Wang, Zongzhe Li, Jinfa Tou, Lei Yu, Weibing Tang, Yuanmei Liu, Xuewu Jiang, Hongxia Ren, Mei Yu, Qiang Yin, Xiang Liu, Zhilin Xu, Dianming Wu, Chunlei Jiao, Donghai Yu, Xiaojuan Wu, Tianqi Zhu, Jixin Yang, Lei Xiang, Jing Wang, Qiong Wang, Bingyan Zhou, Di Wang, Ke Chen, Handan Mao, Bin Wang, Jianghua Zhan, Cong-Yi Wang, Wanjiang Zeng, Feng Chen, Bo Xiong, Jiexiong Feng

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引用次数: 0

Abstract

Background: The enteric nervous system (ENS), which arises from enteric neural crest cells (ENCCs), plays important roles in many aspects of gastrointestinal tract function, including motility, secretions, blood flow and hormone release. Defects in ENS development could lead to a broad range of disorders, including Hirschsprung's disease (HSCR), which is characterized by missing nerve cells in the distal segment of the colon. Here, we identify EMB as an evolutionarily conserved regulator of ENS development.

Methods: We first examined EMB expression in human and mouse intestines using scRNA-seq data and immunofluorescence staining. To investigate its role in ENS development, we constructed Emb-knockout zebrafish and mouse models. To explore the underlying mechanisms, we focused on ENCCs and analyzed their proliferation and migration using migration assays in explant guts and organoid cultures. Finally, we assessed rare EMB variants in a cohort of HSCR patients.

Results: In zebrafish, loss of emb leads to a decrease number of enteric neurons and impaired intestinal transit ability. In mice, knockout of Emb causes HSCR-like phenotypes and defects. In vitro experiments, including explant mouse gut and organoid cultures, show that EMB is required for both the proliferation and migration of ENCCs. Mechanistically, EMB binds to and recruits the phosphatase complex PP2A to the cellular membrane to facilitate the activation of PI3K-AKT pathway, thereby promoting ENCCs development. Indeed, application of PI3K or AKT agonists partially restores the ENS developmental defects in zebrafish emb mutants. Furthermore, rare variants of EMB may potentially contribute to the pathology of HSCR in humans.

Conclusions: EMB is required for ENS development by regulating the proliferation and migration of the ENCCs. Mechanistically, EMB recruits PP2A to the cell membrane, reducing cytoplasmic dephosphorylation activity and promoting the activation of the PI3K signaling pathway.

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EMB对由PI3K信号介导的肠神经系统发育至关重要。

背景：肠神经系统（enteric nervous system， ENS）由肠神经嵴细胞（enteric neural crest cells, ENCCs）演变而来，在胃肠道运动、分泌、血流和激素释放等诸多方面发挥着重要作用。ENS发育的缺陷可能导致广泛的疾病，包括先天性巨结肠病（HSCR），其特征是结肠远端神经细胞缺失。在这里，我们确定EMB是ENS发展的进化保守调节因子。方法：我们首先使用scRNA-seq数据和免疫荧光染色检测人和小鼠肠道中EMB的表达。为了研究其在ENS发育中的作用，我们构建了emb敲除斑马鱼和小鼠模型。为了探索潜在的机制，我们重点研究了ENCCs，并通过外植体肠道和类器官培养的迁移实验分析了它们的增殖和迁移。最后，我们评估了一组HSCR患者中罕见的EMB变异。结果：在斑马鱼中，emb的缺失导致肠神经元数量减少，肠转运能力受损。在小鼠中，敲除Emb会导致hsr样表型和缺陷。体外实验，包括外植体小鼠肠道和类器官培养，表明EMB对ENCCs的增殖和迁移都是必需的。从机制上讲，EMB结合并招募磷酸酶复合物PP2A到细胞膜，促进PI3K-AKT通路的激活，从而促进ENCCs的发展。事实上，应用PI3K或AKT激动剂可以部分恢复斑马鱼胚胎突变体的ENS发育缺陷。此外，罕见的EMB变异可能潜在地促进人类HSCR的病理。结论：EMB通过调节ENCCs的增殖和迁移，是ENS发展所必需的。从机制上讲，EMB将PP2A招募到细胞膜上，降低细胞质去磷酸化活性，促进PI3K信号通路的激活。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Genome Medicine GENETICS & HEREDITY-

CiteScore

20.80

自引率

0.80%

发文量

128

审稿时长

6-12 weeks

期刊介绍： Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.