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

Area of Science:

• Developmental biology
• Neuroscience
• Genetics

Background:

• The enteric nervous system (ENS), derived from enteric neural crest cells (ENCCs), governs gastrointestinal functions.
• Developmental defects in the ENS can lead to disorders like Hirschsprung's disease (HSCR).
• EMB is identified as a conserved regulator of ENS development.

Purpose of the Study:

• To investigate the role of EMB in the development of the enteric nervous system.
• To explore the molecular mechanisms by which EMB influences ENCCs.
• To assess the potential contribution of EMB variants to HSCR.

Main Methods:

• Examined EMB expression in human and mouse intestines via scRNA-seq and immunofluorescence.
• Generated and analyzed Emb-knockout zebrafish and mouse models.
• Investigated ENCC proliferation and migration using explant guts and organoid cultures; assessed rare EMB variants in HSCR patients.

Main Results:

• Loss of EMB in zebrafish and mice resulted in decreased enteric neurons, impaired intestinal transit, and HSCR-like phenotypes.
• EMB is essential for both proliferation and migration of ENCCs.
• EMB recruits PP2A to the cell membrane, activating the PI3K-AKT pathway and promoting ENCC development; PI3K/AKT agonists partially rescued defects.

Conclusions:

• EMB is indispensable for ENS development, controlling ENCC proliferation and migration.
• EMB functions by recruiting PP2A to the cell membrane, facilitating PI3K signaling.
• Rare EMB variants may play a role in the pathogenesis of HSCR.