{"title":"EMB对由PI3K信号介导的肠神经系统发育至关重要。","authors":"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","doi":"10.1186/s13073-025-01538-1","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"102"},"PeriodicalIF":10.4000,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465749/pdf/","citationCount":"0","resultStr":"{\"title\":\"EMB is essential for enteric nervous system development mediated by PI3K signaling.\",\"authors\":\"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\",\"doi\":\"10.1186/s13073-025-01538-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":12645,\"journal\":{\"name\":\"Genome Medicine\",\"volume\":\"17 1\",\"pages\":\"102\"},\"PeriodicalIF\":10.4000,\"publicationDate\":\"2025-09-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465749/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genome Medicine\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s13073-025-01538-1\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Medicine","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13073-025-01538-1","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
EMB is essential for enteric nervous system development mediated by PI3K signaling.
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.
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.
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