ECEESPE2025 Poster Presentations MTEabolism, Nutrition and Obesity (125 abstracts)
AIP deficiency in zebrafish causes loss of intestinal epithelial differentiation via disrupted wnt signaling
Xian Wang 1 , 2 , Oliver Haworth 1 , 3 , Sayka Barry 1 , Adele Leggieri 2 , charlotte Hall 1 , Joanne Martin 4 , Marta Korbonits 1 & Caroline Brennan 2
1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; 2School of Biological and Behavioural Sciences, Queen Mary University of London, London, United Kingdom; 3School of Life Sciences, University of Westminster, London, United Kingdom; 4Centre for Genomics and Child Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
JOINT1692
Background: Heterozygous mutations in the chaperone Aryl Hydrocarbon Receptor Interacting Protein (AIP) are implicated in approximately 10% of familial isolated pituitary adenomas, while homozygous mutations result in embryonic lethality in mice, Drosophila and C. elegans models. To date, five human patients with complete loss of AIP function have been identified, exhibiting, among other features, failure to thrive and severe diarrhoea requiring parenteral nutrition.
Methods: In this study, we generated an aip loss-of-function zebrafish model using CRISPR-Cas9 gene editing to investigate the molecular and physiological consequences of AIP deficiency. Survival rates were monitored daily, and intestinal morphology was assessed via haematoxylin and eosin (H&E) staining. Cellular proliferation was evaluated through PCNA immunohistochemistry, while stem cell populations were characterized using in situ hybridization for specific mRNA markers. Cell morphology was assessed via immunofluorescence. Gene expression of WNT signalling pathway was analysed through RNA sequencing (RNA-seq) and quantitative PCR (RT-qPCR) performed. Food ingestion capacity was evaluated using a feeding assay.
Results: aip mutant zebrafish exhibited growth retardation from 6 days post-fertilization (dpf). Although they demonstrated the ability to capture food, mutants displayed impaired digestion and absorption, possibly due to a failure of intestinal epithelial differentiation at 5 dpf. By 4 dpf, overactivation of WNT signalling and increased cellular proliferation were observed in mutants, accompanied by a marked deficiency in intestinal stem cells and disrupted cell elongation. By 7 dpf, aip knockout fish exhibited a notable increase in bi-nucleated cells within the intestinal epithelium, along with a significant reduction in the number of Goblet cells.
Conclusion: These findings suggest that loss of aip results in intestinal stem cell depletion, impaired cellular differentiation, and defects in cell elongation, partly mediated through dysregulation of the WNT signalling pathway.
Keywords aip, zebrafish, wnt, proliferation, stem cells.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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