PUBLICATION
circANKRD12/circTIMMDC1 synergistically regulates enteric neural crest cell migration via miR-181b-5p-PROX1-NOTCH1 axis in Hirschsprung's disease
- Authors
- Fu, R., Wang, C., Xu, Z., Zhai, J., Zhao, Y., Liu, X., Zhou, Y., Gu, P., Pan, W., Wang, Y., Cai, W.
- ID
- ZDB-PUB-250803-4
- Date
- 2025
- Source
- Pediatric Research : (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 40750918 Full text @ Pediatr. Res.
Citation
Fu, R., Wang, C., Xu, Z., Zhai, J., Zhao, Y., Liu, X., Zhou, Y., Gu, P., Pan, W., Wang, Y., Cai, W. (2025) circANKRD12/circTIMMDC1 synergistically regulates enteric neural crest cell migration via miR-181b-5p-PROX1-NOTCH1 axis in Hirschsprung's disease. Pediatric Research. :. Epub ahead of print.
Abstract
Background Circular RNAs (circRNAs) are implicated in Hirschsprung's disease (HSCR), a genetic disorder caused by defective migration and proliferation of enteric neural crest cells (ENCCs).
Methods Expression patterns of circANKRD12 and circTIMMDC1, and related molecules in the miR-181b-5p-PROX1-NOTCH1 axis were analyzed in human and mouse fetal intestines and HSCR patient tissues. Functional assays, including in vitro neural cell experiments, ex vivo ENCC explant, and in vivo zebrafish models, were conducted to assess the effects on neural cell behavior.
Results circANKRD12 and circTIMMDC1 were significantly downregulated in HSCR patient tissues. Single-cell analysis confirmed PROX1, NOTCH1, and HES1 expression in ENCCs from human and mouse fetal intestines. Both circRNAs synergistically regulated PROX1 by sponging miR-181b-5p, activating the NOTCH1-HES1 signaling pathway, and enhancing neural cell migration. Knockdown of these circRNAs impaired ENCC proliferation and migration. Zebrafish lacking prox1a showed reduced enteric neurons.
Conclusions circANKRD12 and circTIMMDC1 synergistically modulate ENCC function via the miR-181b-5p-PROX1-NOTCH1 axis, providing insights into HSCR pathogenesis and potential therapies.
Impact The study identifies circANKRD12 and circTIMMDC1 as pathogenic circRNAs in HSCR, revealing their synergistic effects on regulating ENCC migration. The study reveals that prox1a (human PROX1 homolog) deficiency in zebrafish induces HSCR-like phenotypes. The study elucidates the detailed mechanistic insights into the circANKRD12/circTIMMDC1-miR-181b-5p-PROX1-NOTCH1 axis in ENCC migration. The study contributes to the development of diagnostic tools and therapies targeting the ceRNA network in HSCR, alongside improved prenatal screening methods for early detection.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping