ArticleCellular and molecular gastroenterology and hepatology2019
Gfra1 Underexpression Causes Hirschsprung's Disease and Associated Enterocolitis in Mice.
Article in Cellular and molecular gastroenterology and hepatology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 32 citations in OpenAlex.
- Exosomes derived from M1-macrophage promote enteric neuronal injury via MMP8-TGF-β pathway.Journal of advanced research · 2026Article
- Converging neurotrophic-immune signaling in autism spectrum disorder: integrative roles of klotho, GDNF/GFRA-1, IGF-1 and GLP-1 pathways.Metabolic brain disease · 2026Review
- Mucus and mucin: changes in the mucus barrier in disease states.Tissue barriers · 2025Review
- Efficient enzyme-free method to assess the development and maturation of the innate and adaptive immune systems in the mouse colon.Scientific reports · 2024Article
- Clinical and Genetic Correlation in Neurocristopathies: Bridging a Precision Medicine Gap.Journal of clinical medicine · 2024Review
- Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis.International journal of molecular sciences · 2023Review
- Neonatal development of intestinal neuroimmune interactions.Trends in neurosciences · 2022Review
- Association betweenTranslational pediatrics · 2022Article
- Article
- TheInternational journal of molecular sciences · 2021Article
- Association Analysis of Variants ofFrontiers in cell and developmental biology · 2021Article
- Analysis of enteric nervous system and intestinal epithelial barrier to predict complications in Hirschsprung's disease.Scientific reports · 2020Article
- FAM3D is essential for colon homeostasis and host defense against inflammation associated carcinogenesis.Nature communications · 2020Article
- Germ-free housing conditions do not affect aortic root and aortic arch lesion size of late atherosclerotic low-density lipoprotein receptor-deficient mice.Gut microbes · 2020Article
- RET Receptor Tyrosine Kinase: Role in Neurodegeneration, Obesity, and Cancer.International journal of molecular sciences · 2020Review
- Review
- The Role of the Gastrointestinal Mucus System in Intestinal Homeostasis: Implications for Neurological Disorders.Frontiers in cellular and infection microbiology · 2020Review
- Chronic Megacolon Presenting in Adolescents or Adults: Clinical Manifestations, Diagnosis, and Genetic Associations.Digestive diseases and sciences · 2019Review
- [Effect of enhancer of zeste homolog 2 on the expression of glial cell line-derived neurotrophic factor family receptor α-1 in the colon tissue of children with Hirschsprung's disease].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2019Article
- Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease.Frontiers in molecular neuroscience · 2019Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
BACKGROUND &
aimsRET, the receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands, is the most frequently mutated gene in congenital aganglionic megacolon or Hirschsprung's disease (HSCR). The leading cause of mortality in HSCR is HSCR-associated enterocolitis (HAEC), which is characterized by altered mucin composition, mucin retention, bacterial adhesion to enterocytes, and epithelial damage, although the order of these events is obscure. In mice, loss of GDNF signaling leads to a severely underdeveloped enteric nervous system and neonatally fatal kidney agenesis, thereby precluding the use of these mice for modeling postnatal HSCR and HAEC. Our aim was to generate a postnatally viable mouse model for HSCR/HAEC and analyze HAEC etiology.
methodsGDNF family receptor alpha-1 (GFRa1) hypomorphic mice were generated by placing a selectable marker gene in the sixth intron of the Gfra1 locus using gene targeting in mouse embryonic stem cells.
resultsWe report that 70%-80% reduction in GDNF co-receptor GFRa1 expression levels in mice results in HSCR and HAEC, leading to death within the first 25 postnatal days. These mice mirror the disease progression and histopathologic findings in children with untreated HSCR/HAEC.
conclusionsIn GFRa1 hypomorphic mice, HAEC proceeds from goblet cell dysplasia, with abnormal mucin production and retention, to epithelial damage. Microbial enterocyte adherence and tissue invasion are late events and therefore unlikely to be the primary cause of HAEC. These results suggest that goblet cells may be a potential target for preventative treatment and that reduced expression of GFRa1 may contribute to HSCR susceptibility.
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