Conditional cell ablation by tight control of caspase-3 dimerization in transgenic mice.
Studying the effects of the loss of a specific cell type is a powerful approach in biology. Here we present a method based on the controlled activation of the apoptotic machinery. We expressed a modified caspase-3-containing chemical inducer of dimerization (CID)-binding sites in the livers of transgenic mice. In the absence of CID, no liver injury was detectable, underlining the absence of leakage in our system. In contrast, injection of the CID produced activation of the chimeric caspase-3, which led to a dose-dependent pure hepatocyte ablation with subsequent regeneration. This method is effective in both growing and nongrowing cells, and is therefore applicable to a wide range of cells and tissues. Moreover, because apoptosis has been described in numerous pathological circumstances, this system is useful for generating mouse models of human disorders as well as for studying the recovery or regeneration of tissues after cell loss.
Mallet
Vincent O
VO
Department of Genetics, Development and Molecular Pathology, Cochin Institute, 24 rue du Faubourg Saint Jacques, 75014 Paris, France.
Mitchell
Claudia
C
Guidotti
Jacques-Emmanuel
JE
Jaffray
Patrick
P
Fabre
Monique
M
Spencer
David
D
Arnoult
Damien
D
Kahn
Axel
A
Gilgenkrantz
Hélène
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007274:Injections, Intraperitoneal; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D016343:Monitoring, Intraoperative; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012016:Reference Values; D016559:Tacrolimus / Q000008:administration & dosage* / Q000031:analogs & derivatives*
C463061:AP20187; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D016559:Tacrolimus