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

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; 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

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

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, 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^*

^*Corresponding author for this work

QBRI - Diabetes Research Center

Huazhong University of Science and Technology
Hubei Clinical Center of Hirschsprung’s Disease and Allied Disorders
The First Affiliated Hospital of Zhengzhou University
Zhejiang University
Nanjing Children’s Hospital Affiliated Nanjing Medical University
Zunyi Medical University
The Second Affiliated Hospital of Shantou University Medical College
Children’s Hospital of Shanxi
Guiyang Maternal and Child Health Hospital
Hunan Children's Hospital
Anhui Provincial Children’s Hospital
The First Affiliated Hospital of Harbin Medical University
Fujian Medical University
Shenzhen Children's Hospital
Tianjin University

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Article number	102
Journal	Genome Medicine
Volume	17
Issue number	1
DOIs	https://doi.org/10.1186/s13073-025-01538-1
Publication status	Published - Dec 2025

Keywords

EMB
Enteric nervous system
Hirschsprung’s Disease
Neural crest cell
PI3K pathway

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10.1186/s13073-025-01538-1

Cite this

@article{8ca5703f2d6b42d48e40e9594d00c9c3,

title = "EMB is essential for enteric nervous system development mediated by PI3K signaling",

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{\textquoteright}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.",

keywords = "EMB, Enteric nervous system, Hirschsprung{\textquoteright}s Disease, Neural crest cell, PI3K pathway",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1186/s13073-025-01538-1",

language = "English",

volume = "17",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central Ltd",

number = "1",

}

Li, Z, Zhuansun, D, Meng, X, Yang, H, Xiao, J, Chen, Y, Wang, J, Yu, X, Li, Z, You, J, Chen, X, Feng, C, Wu, L, Chu, X, Duan, W, Wang, K, Li, Z, Tou, J, Yu, L, Tang, W, Liu, Y, Jiang, X, Ren, H, Yu, M, Yin, Q, Liu, X, Xu, Z, Wu, D, Jiao, C, Yu, D, Wu, X, Zhu, T, Yang, J, Xiang, L, Wang, Q, Zhou, B, Wang, D, Chen, K, Mao, H, Wang, B, Zhan, J, Wang, CY, Zeng, W, Chen, F, Xiong, B & Feng, J 2025, 'EMB is essential for enteric nervous system development mediated by PI3K signaling', Genome Medicine, vol. 17, no. 1, 102. https://doi.org/10.1186/s13073-025-01538-1

TY - JOUR

T1 - EMB is essential for enteric nervous system development mediated by PI3K signaling

AU - Li, Zhi

AU - Zhuansun, Didi

AU - Meng, Xinyao

AU - Yang, Heying

AU - Xiao, Jun

AU - Chen, Yingjian

AU - Wang, Jing

AU - Yu, Xiaosi

AU - Li, Zejian

AU - You, Jingyi

AU - Chen, Xuyong

AU - Feng, Chenzhao

AU - Wu, Luyao

AU - Chu, Xufeng

AU - Duan, Weicheng

AU - Wang, Kang

AU - Li, Zongzhe

AU - Tou, Jinfa

AU - Yu, Lei

AU - Tang, Weibing

AU - Liu, Yuanmei

AU - Jiang, Xuewu

AU - Ren, Hongxia

AU - Yu, Mei

AU - Yin, Qiang

AU - Liu, Xiang

AU - Xu, Zhilin

AU - Wu, Dianming

AU - Jiao, Chunlei

AU - Yu, Donghai

AU - Wu, Xiaojuan

AU - Zhu, Tianqi

AU - Yang, Jixin

AU - Xiang, Lei

AU - Wang, Qiong

AU - Zhou, Bingyan

AU - Wang, Di

AU - Chen, Ke

AU - Mao, Handan

AU - Wang, Bin

AU - Zhan, Jianghua

AU - Wang, Cong Yi

AU - Zeng, Wanjiang

AU - Chen, Feng

AU - Xiong, Bo

AU - Feng, Jiexiong

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

KW - EMB

KW - Enteric nervous system

KW - Hirschsprung’s Disease

KW - Neural crest cell

KW - PI3K pathway

UR - https://www.scopus.com/pages/publications/105017185841

U2 - 10.1186/s13073-025-01538-1

DO - 10.1186/s13073-025-01538-1

M3 - Article

C2 - 40999499

AN - SCOPUS:105017185841

SN - 1756-994X

VL - 17

JO - Genome Medicine

JF - Genome Medicine

IS - 1

M1 - 102

ER -

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

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