title: Generation and Characterisation of a Pax8-CreERT2 Transgenic Line and a Slc22a6-CreERT2 Knock-In Line for Inducible and Specific Genetic Manipulation of Renal Tubular Epithelial Cells.
abstract: Genetically relevant mouse models need to recapitulate the hallmarks of human disease by permitting spatiotemporal gene targeting. This is especially important for replicating the biology of complex diseases like cancer, where genetic events occur in a sporadic fashion within developed somatic tissues. Though a number of renal tubule targeting mouse lines have been developed their utility for the study of renal disease is limited by lack of inducibility and specificity. In this study we describe the generation and characterisation of two novel mouse lines directing CreERT2 expression to renal tubular epithelia. The Pax8-CreERT2 transgenic line uses the mouse Pax8 promoter to direct expression of CreERT2 to all renal tubular compartments (proximal and distal tubules as well as collecting ducts) whilst the Slc22a6-CreERT2 knock-in line utilises the endogenous mouse Slc22a6 locus to specifically target the epithelium of proximal renal tubules. Both lines show high organ and tissue specificity with no extrarenal activity detected. To establish the utility of these lines for the study of renal cancer biology, Pax8-CreERT2 and Slc22a6-CreERT2 mice were crossed to conditional Vhl knockout mice to induce long-term renal tubule specific Vhl deletion. These models exhibited renal specific activation of the hypoxia inducible factor pathway (a VHL target). Our results establish Pax8-CreERT2 and Slc22a6-CreERT2 mice as valuable tools for the investigation and modelling of complex renal biology and disease.
authors: Department of Oncology, University of Cambridge, CRUK Cambridge institute, Cambridge, United Kingdom.
authors: Judit
authors: J
authors: Espana-Agusti
authors: Transgenics Facility, University of Cambridge, CRUK Cambridge institute, Cambridge, United Kingdom.
authors: Xiangang
authors: X
authors: Zou
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
authors: Kim
authors: K
authors: Wong
authors: Cytogenetics Facility, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
authors: Beiyuan
authors: B
authors: Fu
authors: Cytogenetics Facility, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
authors: Fengtang
authors: F
authors: Yang
authors: Department of Oncology, University of Cambridge, CRUK Cambridge institute, Cambridge, United Kingdom.
authors: David A
authors: DA
authors: Tuveson
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
authors: David J
authors: DJ
authors: Adams
authors: Department of Oncology, University of Cambridge, CRUK Cambridge institute, Cambridge, United Kingdom.
authors: Athena
authors: A
authors: Matakidou
mesh_terms: D000818:Animals; D022202:Chromosomes, Artificial, Bacterial; D004847:Epithelial Cells / Q000166:cytology*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D055879:Gene Knock-In Techniques; D005838:Genotype; D000860:Hypoxia; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D019426:Integrases; D007684:Kidney Tubules / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D027362:Organic Anion Transport Protein 1 / Q000235:genetics*; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013629:Tamoxifen / Q000737:chemistry; D019076:Transgenes
chemical_list: D047628:Estrogen Receptor alpha; D027362:Organic Anion Transport Protein 1; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; C105033:Slc22a6 protein, mouse; D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases