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Intestinal phenotype of variable-weight cystic fibrosis knockout mice
Juan C Canale-Zambrano1, Maya C Poffenberger, Sean M Cory
1Meakins-Christie Laboratories, 3626 St. Urbain, Montreal, PQ, Canada.
Abstract:
Cystic fibrosis (CF) transmembrane conductance regulator (Cftr) knockout mice present the clinical features of low body weight and intestinal disease permitting an assessment of the interrelatedness of these phenotypes in a controlled environment. To identify intestinal alterations that are affected by body weight in CF mice, the histological phenotypes of crypt-villus axis height, goblet cell hyperplasia, mast cell infiltrate, crypt cell proliferation, and apoptosis were measured in a population of 12-wk-old (C57BL/6 x BALB/cJ) F2 Cftr(tm1UNC) and non-CF mice presenting a range of body weight. In addition, cardiac blood samples were assessed, and gene expression profiling of the ileum was completed. Crypt-villus axis height decreased with increasing body weight in CF but not control mice. Intestinal crypts from CF mice had fewer apoptotic cells, per unit length, than did non-CF mice, and normalized cell proliferation was similar to control levels. Goblet cell hyperplasia and mast cell infiltration were increased in the CF intestine and identified to be independent of body weight. Blood triglyceride levels were found to be significantly lower in CF mice than in control mice but were not dependent on CF mouse weight. By expression profiling, genes of DNA replication and lipid metabolism were among those altered in CF mice relative to non-CF controls, and no differences in gene expression were measured between samples from CF mice in the 25th and 75th percentile for weight. In this CF mouse model, crypt elongation, due to an expanded proliferative zone and decreased apoptosis, was identified to be dependent on body weight.
Insights
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) knockout mice show that intestinal crypt elongation is linked to body weight. This CFTR dysfunction impacts crypt cell apoptosis and proliferation, affecting overall intestinal health.
Area of Science:
- Gastroenterology
- Genetics
- Physiology
Background:
- Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) knockout mice exhibit low body weight and intestinal disease.
- Understanding the relationship between these CFTR-related phenotypes is crucial for disease modeling.
Purpose of the Study:
- To investigate how body weight influences intestinal alterations in CFTR-deficient mice.
- To identify specific histological and molecular changes in the intestine related to CFTR dysfunction and body weight.
Main Methods:
- Histological analysis of crypt-villus axis height, goblet cell hyperplasia, mast cell infiltration, crypt cell proliferation, and apoptosis in CFTR knockout and control mice.
- Assessment of blood triglyceride levels and gene expression profiling of the ileum.
Main Results:
- Crypt-villus axis height decreased with increasing body weight in CFTR knockout mice.
- CFTR knockout mice had reduced apoptosis and similar normalized proliferation in intestinal crypts compared to controls.
- Goblet cell hyperplasia and mast cell infiltration were increased in CFTR knockout mice, independent of body weight.
- Lower blood triglyceride levels were observed in CFTR knockout mice, unrelated to their body weight.
- Gene expression profiling revealed alterations in DNA replication and lipid metabolism pathways in CFTR knockout mice.
Conclusions:
- In this CFTR mouse model, crypt elongation is dependent on body weight, driven by an expanded proliferative zone and decreased apoptosis.
- Intestinal alterations in CFTR knockout mice are complex and influenced by both CFTR function and body weight, with some factors like goblet cell hyperplasia being independent of weight.
