Cystic Fibrosis Mouse Model

General Characteristics

Lifespan: 1-2 years

Gestation time: 20 days

Litter Size: 4-8 (dependent upon background)

Age to sexual maturity: 6 weeks

Adult weight: ~15-30 grams

Mouse

The Cystic Fibrosis Model

The first CF mouse model was published in 1992.1 Since 1992, more than 20 different mouse models for the study of CF have been created (see Available Mutated Strains). The CF mouse model has assisted CF researchers in studying disease manifestations ranging from intestinal obstruction and lung disease to immune function and colon cancer.

General Husbandry of CF Mice

Production of CF mice

Many mouse models, including the majority of Cftr mouse mutations, were created using gene targeting through homologous recombination in mouse embryonic stem cells. Newer models have utilized CRISPR/Cas gene editing through homology-directed repair in one-cell embryos. Once the mutation is created, CF mice are typically produced by breeding mice carrying one mutated Cftr allele, or heterozygous mice, which results in the birth of mice in the expected Mendelian ratio (1:2:1). CF male and female mice do not typically breed well. Although some CF male mice can produce offspring, the number of pups per litter are usually quite reduced. CF female mice rarely give birth. This infertility in both sexes is dependent on the severity of the Cftr mutation.

Maintenance

CF mice are prone to intestinal obstruction leading to death. There are several different ways to alleviate intestinal obstruction through diet. The most effective way is to use laxative (colyte) in their drinking water. Another way is to use a total liquid diet called peptamen. However peptamen needs to be changed daily due to it going rancid, while colyte can be changed weekly and used with standard solid chow. CF mice are also much smaller than their littermates. This size discrepancy may require up to an extra week with the dam before weaning compared to their littermates.

Disease Manifestations

 

Intestinal Disease

The most severe CF manifestation in mice is intestinal obstruction leading to death. This intestinal obstruction is due to a buildup of luminal mucus making it harder and harder for the movement of intestinal contents. The majority of death from intestinal obstruction occurs between 15-30 days of life as this is when mice start eating solid chow and are weaned from the dam. As mentioned above, this incidence of this obstruction can be reduced through either laxative in the drinking water or a liquid diet.

Survival

 

Growth

CF mice have reduced growth prenatally, which continues throughout life. CF mice range from 10% to 50% of their littermates weights depending on age, sex, and severity of the mutation. The origin(s) of this reduced growth in CF mice is still up for debate as there is no evidence for a pulmonary or pancreatic origin. Gut-corrected CF mice also display reduced growth which refutes an intestinal origin as well.

Growth

 

Pulmonary Disease

Initial pulmonary characterizations of CF mouse models were disappointing due to the lack of severity compared to human patients. CF mice do not display severe lung disease as observed in humans and do not die due to any pulmonary complications. However, more recent studies have shown CF-like manifestations modeling early lung disease. CF mouse models display a pulmonary phenotype characterized by increased respiratory rate and variability and changes in pulmonary mechanics (decreased airway compliance, increased airway and tissue elastance, and increased tissue damping). There is also evidence of structural anatomical differences in the small airways, with CF mice displaying increased air spaces indicative of parenchymal and alveolar changes. The impaired ability to stretch and expand the lung compartment and increased distances between gas exchange surfaces is similar to the early lung phenotype of CF patients. In addition, CF mice have an increased inflammatory and immune response following infection with known CF pathogens. Recently, spontaneous lung infections in CF mice with Bordetella pseudohinzii have been reported and CF mice were unable to clear these infections on their own. These findings are also consistent with CF patients, who develop chronic airway infections and demonstrate increased immune responses to infection but with decreased clearance ability.

 

Hepatic Disease

Some CF mouse strains have been reported to have biliary cirrhosis with incidence increasing with age, while other CF strains are not observed to have any liver abnormalities.

 

Pancreatic Disease

There has been no evidence for exocrine pancreatic insufficiency in younger CF mice. Pancreatic pathology has been observed in older CF mice (at least 9 months of age) with progressive obstruction of the small ducts and acini. However, there is no data to date on whether this progression leads to exocrine pancreatic destruction with further aging.

 

Reproductive Dysfunction

Male: There have been varying reports on male fertility and the presence or absence of the vas deferens in CF mice. In general, most CF mouse strains do produce a few males that can breed and produce offspring but at a reduced capacity (fewer sperm and fewer pups).

Female: CF female mice typically do not reproduce. CF female mice have high amounts of mucus in the uterus impeding sperm travel and abnormal hormone production leading to spurious cycling and reduced ovulation.

 

Other Manifestations

Upper incisors of CF mice are chalky white compared to the yellow of their littermates. The difference in color can be detected at around 4 weeks of age and is thought to be due to abnormal enamel development in CF mice. This manifestation is useful for verifying that the mouse is CF in combination with any genotyping that is completed.

Available Mutated Strains

CF mouse strain Mutation Reference Availability
Cftrtm1Unc S489X [1] A,B
Cftrtm1kth F508del [2] A,B
Cftrtm1Cam Exon 10 disruption with HPRT [3] C
Cftrtm2Cam F508del [4] *
Cftrtm1Hsc Exon 1 disruption with Neomycin [5] *
Cftrtm1Hgu Exon 10 disruption with Neomycin [6] *
Cftrtm1Bay Exon 3 insertional duplication [7] *
Cftrtm3Bay Exon 2 disruption [8] *
Cftrtm1Eur F508del [9] C
Cftrtm3Hgu G551D [10] C
Cftrtm2Hgu G480C [11] *
Cftrtm2Mrc R117H [12] B
Cftrtm1.1Cwr Exon 10 deletion [13] B
Cftrtm1Cwr Exon10 floxed [13] B
Cftrtm2Cwr Exon 10 inverted floxed [14] B
Cftrem3Cwr G542X [15] B

(Note: The strains above use legacy numbering for exons. Newer publications will sometimes refer to the legacy exon 10 now as exon 11.)

Available Transgenic Strains

CF mouse strain Transgene Reference Availability
Tg(FABPCFTR) CFTR [16] A,B
Tg(FABPCFTRG542X) CFTRG542X [17] C
Tg(CCSPScnn1b) Scnn1B [18] A,B

A = Jackson Laboratories

B = Case Western Reserve University Mouse Models Core

C = University of Alabama at Birmingham Mouse Models Core

* = No availability known. Please contact the authors of the indicated reference.

Contact for Information or Questions about this Model

e-mail: cfmice@case.edu

website: www.cfmice.org

References and Reviews

1. Snouwaert, J.N., et al., An animal model for cystic fibrosis made by gene targeting. Science, 1992. 257(5073): p. 1083-8.
2. Zeiher, B.G., et al., A mouse model for the delta F508 allele of cystic fibrosis. J Clin Invest, 1995. 96(4): p. 2051-64.
3. Ratcliff, R., et al., Production of a severe cystic fibrosis mutation in mice by gene targeting. Nat Genet, 1993. 4(1): p. 35-41.
4. Colledge, W.H., et al., Generation and characterization of a delta F508 cystic fibrosis mouse model. Nat Genet, 1995. 10(4): p. 445-52.
5. Rozmahel, R., et al., Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet, 1996. 12(3): p. 280-7.
6. Dorin, J.R., et al., Cystic fibrosis in the mouse by targeted insertional mutagenesis. Nature, 1992. 359(6392): p. 211-5.
7. O'Neal, W.K., et al., A severe phenotype in mice with a duplication of exon 3 in the cystic fibrosis locus. Hum Mol Genet, 1993. 2(10): p. 1561-9.
8. Hasty, P., et al., Severe phenotype in mice with termination mutation in exon 2 of cystic fibrosis gene. Somat Cell Mol Genet, 1995. 21(3): p. 177-87.
9. van Doorninck, J.H., et al., A mouse model for the cystic fibrosis delta F508 mutation. Embo J, 1995. 14(18): p. 4403-11.
10. Delaney, S.J., et al., Cystic fibrosis mice carrying the missense mutation G551D replicate human genotype-phenotype correlations. Embo J, 1996. 15(5): p. 955-63.
11. Dickinson, P., et al., The severe G480C cystic fibrosis mutation, when replicated in the mouse, demonstrates mistrafficking, normal survival and organ-specific bioelectrics. Hum Mol Genet, 2002. 11(3): p. 243-51.
12. van Heeckeren, A.M., et al., Role of Cftr genotype in the response to chronic Pseudomonas aeruginosa lung infection in mice. Am J Physiol Lung Cell Mol Physiol, 2004. 287(5): p. L944-52.
13. Hodges, C.A., et al., Generation of a conditional null allele for Cftr in mice. Genesis, 2008. 46(10): p. 546-52.
14. Hodges, C.A., et al., Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol, 2011. 301(3): p. G528-36.
15. McHugh, D.R., et al., A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies. PLoS One, 2018. 13(6): p. e0199573.
16. Zhou, L., et al., Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. Science, 1994. 266(5191): p. 1705-8.
17. Du, M., et al., Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. J Mol Med (Berl), 2002. 80(9): p. 595-604.
18. Mall, M., et al., Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med, 2004. 10(5): p. 487-93.