2. Academic Validation
  3. EMB is essential for enteric nervous system development mediated by PI3K signaling

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

  • Genome Med. 2025 Sep 25;17(1):102. doi: 10.1186/s13073-025-01538-1.
Zhi Li # 1 2,  Didi Zhuansun # 1 2,  Xinyao Meng # 1 2,  Heying Yang # 3,  Jun Xiao # 1 2,  Yingjian Chen # 1 2,  Jing Wang 1 2,  Xiaosi Yu 1 2,  Zejian Li 1 2,  Jingyi You 1 2,  Xuyong Chen 1 2,  Chenzhao Feng 4,  Luyao Wu 1 2,  Xufeng Chu 5,  Weicheng Duan 5,  Kang Wang 5,  Zongzhe Li 6,  Jinfa Tou 7,  Lei Yu 8,  Weibing Tang 9,  Yuanmei Liu 10,  Xuewu Jiang 11,  Hongxia Ren 12,  Mei Yu 13,  Qiang Yin 14,  Xiang Liu 15,  Zhilin Xu 16,  Dianming Wu 17,  Chunlei Jiao 1 2,  Donghai Yu 1 2,  Xiaojuan Wu 1 2,  Tianqi Zhu 1 2,  Jixin Yang 1 2,  Lei Xiang 1 2,  Jing Wang 1 2,  Qiong Wang 1 2,  Bingyan Zhou 1 2,  Di Wang 1 2,  Ke Chen 1 2,  Handan Mao 1 2,  Bin Wang 18,  Jianghua Zhan 19,  Cong-Yi Wang 20 21,  Wanjiang Zeng 4,  Feng Chen 22,  Bo Xiong 23 24,  Jiexiong Feng 25 26
Affiliations

Affiliations

  • 1 Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
  • 2 Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei, 430030, China.
  • 3 Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
  • 4 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
  • 5 Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
  • 6 Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
  • 7 Department of General Surgery, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
  • 8 Department of Neonatal Surgery, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
  • 9 Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, Jiangsu, 210008, China.
  • 10 Department of Pediatric Surgery, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China.
  • 11 Department of Pediatric Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, China.
  • 12 Department of Neonatal Surgery, Children's Hospital of Shanxi, Taiyuan, Shanxi, 030013, China.
  • 13 Department of Pediatric Surgery, Guiyang Maternal and Child Health Hospital, Guiyang, Guizhou, 550002, China.
  • 14 Department of General Surgery, Hunan Children's Hospital, Changsha, Hunan, 515041, China.
  • 15 Department of Pediatric Surgery, Anhui Provincial Children's Hospital, Hefei, Anhui, 230051, China.
  • 16 Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, China.
  • 17 Department of Pediatric Surgery, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350001, China.
  • 18 Department of General Surgery, Shenzhen Children's Hospital, Shenzhen, Guangdong, 518000, China.
  • 19 Department of Pediatric Surgery, Tianjin Children's Hospital, Tianjin University, Tianjin, 300134, China.
  • 20 The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
  • 21 The Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, 34110, Qatar.
  • 22 Department of Pediatric Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian, 350001, China. cfeng3000@163.com.
  • 23 Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. bxiong@hust.edu.cn.
  • 24 Institute for Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. bxiong@hust.edu.cn.
  • 25 Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. 2002tj0515@hust.edu.cn.
  • 26 Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei, 430030, China. 2002tj0515@hust.edu.cn.
  • # Contributed equally.
PMID: 40999499 DOI: 10.1186/s13073-025-01538-1
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.

Keywords

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

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