PUBLICATION
EMB is essential for enteric nervous system development mediated by PI3K signaling
- Authors
- 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, J., Wang, Q., Zhou, B., Wang, D., Chen, K., Mao, H., Wang, B., Zhan, J., Wang, C.Y., Zeng, W., Chen, F., Xiong, B., Feng, J.
- ID
- ZDB-PUB-250926-16
- Date
- 2025
- Source
- Genome Medicine 17: 102102 (Journal)
- Registered Authors
- Li, Zhi, Xiong, Bo
- Keywords
- EMB, Enteric nervous system, Hirschsprung’s Disease, Neural crest cell, PI3K pathway
- MeSH Terms
-
- Neural Crest/metabolism
- Enteric Nervous System*/embryology
- Enteric Nervous System*/growth & development
- Enteric Nervous System*/metabolism
- Phosphatidylinositol 3-Kinases*/metabolism
- Cell Movement
- Mice, Knockout
- Mice
- Humans
- Signal Transduction*
- Hirschsprung Disease/genetics
- Hirschsprung Disease/metabolism
- Hirschsprung Disease/pathology
- Cell Proliferation
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Zebrafish
- Animals
- PubMed
- 40999499 Full text @ Genome Med.
Citation
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, J., Wang, Q., Zhou, B., Wang, D., Chen, K., Mao, H., Wang, B., Zhan, J., Wang, C.Y., Zeng, W., Chen, F., Xiong, B., Feng, J. (2025) EMB is essential for enteric nervous system development mediated by PI3K signaling. Genome Medicine. 17:102102.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping