circRET-mediated regulation of RET influences enteric neural crest cell development in Hirschsprung disease

Hirschsprung disease (HSCR) is a life-threatening congenital disorder characterized by defective migration and proliferation of enteric neural crest cells (ENCCs), a process in which the receptor tyrosine kinase RET plays a central regulatory role. However, the regulatory mechanisms governing RET expression remain incompletely understood. In the present study, we identify the circular RNA circRET (hsa_circ_0093651) as a critical translational regulator of its parental gene RET and explore its role in HSCR pathogenesis. We demonstrate that circRET is significantly downregulated in the colonic tissues from patients with HSCR and directly binds RET mRNA, modulating RET protein synthesis at the translational level without altering mRNA abundance. Notably, circRET interacts with the coding region of RET mRNA, potentially facilitating its translation. circRET knockdown suppresses RET/AKT signaling and impairs ENCC migration, proliferation, and distal colon colonization. Our study uncovers a novel circRET-mediated regulatory mechanism of its parental gene RET, with potential implications for therapeutic targeting in HSCR.NEW & NOTEWORTHY Hirschsprung disease (HSCR) results from impaired enteric neural crest cell development, in which RET plays a central role. Here, we identify circRET as a translational regulator of RET. circRET is downregulated in HSCR tissues and modulates RET protein by directly binding RET mRNA without affecting mRNA levels. Loss of circRET suppresses RET/AKT signaling and ENCC migration, highlighting a novel regulatory mechanism with therapeutic relevance.