Specific in vivo expression in type II pneumocytes of the jaagsiekte sheep retrovirus long terminal repeat in transgenic mice

AbstractJaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma, a transmissible lung cancer in sheep. Previous experiments in differentiated murine tissue culture cell lines suggested that the disease specificity of JSRV for secretory lung epithelial cells (type II pneumocytes an Clara cells) reflects transcriptional specificity of the viral long terminal repeat (LTR) for these cells. To test this in vivo, transgenic mice carrying the bacterial beta-galactosidase (β-Gal) gene driven by the JSRV LTR were generated. Two transgenic lines showed β-Gal expression in the lungs but not other tissues of F1 animals, although transgene silencing in subsequent generations was a major problem. The cells expressing the transgene were identified by two- and three-color immunofluorescence for marker proteins of type II pneumocytes (surfactant protein C [SPC]) and Clara cells (CC10) as well as for a T7 gene 10 epitope present in the β-Gal reporter. F1 animals from both lines showed transgene expression in type II pneumocytes, but somewhat surprisingly not in Clara cells. Expression was not detected in bronchiolo-alveolar stem cells (BASCs) either. These results indicate that the JSRV LTR is specifically active in type II pneumocytes in the mouse lung, which is consistent with the fact that JSRV-induced OPA tumors in sheep largely have phenotypic markers of type II pneumocytes