Conditional lineage ablation to model human diseases

Paul Lee, Gregory Morley, Qian Huang, Avi Fischer, Stephanie Seiler, James W. Horner, Stephen Factor, Dhananjay Vaidya, José Jalife, Glenn I. Fishman

Research output: Contribution to journalArticlepeer-review

96 Scopus citations


Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.

Original languageEnglish
Pages (from-to)11371-11376
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
StatePublished - 15 Sep 1998


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