Research article

Very mild disease phenotype of congenic Cftr^{TgH(neoim)Hgu} cystic fibrosis mice

Balázs Tóth^1,2 , Martina Wilke³ , Frauke Stanke² , Martina Dorsch⁴ , Silke Jansen² , Dirk Wedekind⁴ , Nikoletta Charizopoulou^2,4 , Alice Bot³ , Marion Burmester¹ , Sabine Leonhard-Marek¹ , Hugo R de Jonge³ , Hans-Jürgen Hedrich⁴ , Gerhard Breves¹ and Burkhard Tümmler²

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

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

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

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

author email corresponding author email

BMC Genetics 2008, 9:28doi: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 Cftr^{TgH(neoim)Hgu} mouse model with a divergent genetic background (129/Sv, C57BL/6, HsdOla:MF1) two inbred mutant mouse strains CF/1-Cftr^{TgH(neoim)Hgu} and CF/3-Cftr^{TgH(neoim)Hgu} had been generated using strict brother × sister mating. CF/1-Cftr^{TgH(neoim)Hgu} and CF/3-Cftr^{TgH(neoim)Hgu} mice were fertile and showed normal growth and lifespan. In this work the Cftr^{TgH(neoim)Hgu} insertional mutation was backcrossed from CF/3-Cftr^{TgH(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-Cftr^{TgH(neoim)Hgu} and CF/3-Cftr^{TgH(neoim)Hgu} and wild type controls.

Results

Under the standardized housing conditions of the animal facility, the four mouse strains CF/1-Cftr^{TgH(neoim)Hgu}, CF/3-Cftr^{TgH(neoim)Hgu}, D2.129P2(CF/3)-Cftr^{TgH(neoim)Hgu} and B6.129P2(CF/3)-Cftr^{TgH(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)-Cftr^{TgH(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-Cftr^{TgH(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.