Endogenous Peptide Derived from c-Cbl-Associated Protein Counteracts Its Inhibitory Effect on Enteric Neural Crest...

Area of Science:

• Developmental Biology
• Gastroenterology
• Molecular Medicine

Background:

• Hirschsprung disease (HSCR) is a congenital condition caused by absent enteric nervous system (ENS) in the distal colon.
• The precise pathogenesis of HSCR, particularly the failure of enteric neural crest cell (ENCC) colonization, is not fully understood.
• c-Cbl-associated protein (CAP) has been identified as upregulated in HSCR tissues.

Purpose of the Study:

• To investigate the role of CAP in HSCR pathogenesis.
• To identify and characterize endogenous peptides that may counteract CAP's effects.
• To explore potential peptide-based therapeutic strategies for HSCR.

Main Methods:

• Analysis of CAP expression in HSCR patient tissues.
• Functional studies using cell cultures and mouse models to assess CAP and peptide effects on ENCC colonization.
• Mass spectrometry and ELISA to identify and quantify CAP-derived peptides (PDCAP).

Main Results:

• CAP is upregulated in aganglionic colon tissues from HSCR patients.
• Overexpressed CAP inhibits ENCC colonization by interacting with flotillin-1 and vinculin.
• An endogenous peptide, PDCAP, derived from CAP, was identified and found to be reduced in HSCR tissues; PDCAP competitively inhibits CAP, promoting ENCC colonization and ENS development in mouse models.

Conclusions:

• Upregulated CAP plays a pathogenic role in HSCR by suppressing ENCC colonization.
• PDCAP acts as a functional antagonist to CAP, promoting ENS development.
• PDCAP represents a potential therapeutic target for Hirschsprung disease.