Open Access Research article

Very mild disease phenotype of congenic CftrTgH(neoim)Hgu cystic fibrosis mice

Balázs Tóth12, Martina Wilke3, Frauke Stanke2, Martina Dorsch4, Silke Jansen2, Dirk Wedekind4, Nikoletta Charizopoulou24, Alice Bot3, Marion Burmester1, Sabine Leonhard-Marek1, Hugo R de Jonge3, Hans-Jürgen Hedrich4, Gerhard Breves1 and Burkhard Tümmler2*

Author Affiliations

1 Physiologisches Institut, Stiftung Tierärztliche Hochschule Hannover, Bischofsholer Damm 15/102, D-30173 Hannover, Germany

2 Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany

3 Department of Biochemistry, Erasmus University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands

4 Zentrales Tierlaboratorium, OE 8600, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany

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BMC Genetics 2008, 9:28  doi:10.1186/1471-2156-9-28

Published: 9 April 2008

Abstract

Background

A major boost to cystic fibrosis disease research was given by the generation of various mouse models using gene targeting in embryonal stem cells. Moreover, the introduction of the same mutation on different inbred strains generating congenic strains facilitated the search for modifier genes. From the original CftrTgH(neoim)Hgu mouse model with a divergent genetic background (129/Sv, C57BL/6, HsdOla:MF1) two inbred mutant mouse strains CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu had been generated using strict brother × sister mating. CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu mice were fertile and showed normal growth and lifespan. In this work the CftrTgH(neoim)Hgu insertional mutation was backcrossed from CF/3-CftrTgH(neoim)Hgu onto the inbred backgrounds C57BL/6J and DBA/2J generating congenic animals in order to clarify the differential impact of the Cftr mutation and the genetic background on the disease phenotype of the cystic fibrosis mutant mice. Clinical and electrophysiological features of the two congenic strains were compared with those of CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu and wild type controls.

Results

Under the standardized housing conditions of the animal facility, the four mouse strains CF/1-CftrTgH(neoim)Hgu, CF/3-CftrTgH(neoim)Hgu, D2.129P2(CF/3)-CftrTgH(neoim)Hgu and B6.129P2(CF/3)-CftrTgH(neoim)Hgu exhibited normal life expectancy. Growth of congenic cystic fibrosis mice was comparable with that of wild type controls. All mice but D2.129P2(CF/3)-CftrTgH(neoim)Hgu females were fertile. Short circuit current measurements revealed characteristic response profiles of the HsdOla:MF1, DBA/2J and C57BL/6J backgrounds in nose, ileum and colon. All cystic fibrosis mouse lines showed the disease-typical hyperresponsiveness to amiloride in the respiratory epithelium. The mean chloride secretory responses to carbachol or forskolin were 15–100% of those of the cognate wild type control animals.

Conclusion

The amelioration of the clinical features and of the basic defect that had emerged during the generation of CF/3-CftrTgH(neoim)Hgu mice was retained in the congenic mice indicating that the Cftr linkage group or other loci shared between the inbred strains contain(s) the major modifier(s) of attenuation of cystic fibrosis symptoms.