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Temporal activation of c‐Jun N‐terminal kinase in adult transgenic heart via cre‐loxP‐mediated DNA recombination
Author(s) -
Petrich Brian G.,
Molkentin Jeffery D.,
Wang Yibin
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0438fje
Subject(s) - cre recombinase , transgene , cre lox recombination , genetically modified mouse , biology , site specific recombination , gene , microbiology and biotechnology , kinase , gene expression , regulation of gene expression , activator (genetics) , recombinase , genetics , recombination
ABSTRACT Using a cre‐loxP‐mediated gene‐switch approach, we achieved targeted JNK activation in adult hearts. A transgenic model is established carrying a floxed gene‐switch construct that directs GFP marker gene expression in the absence of DNA recombination between two loxP sites. A tamoxifen‐inducible Cre recombinase was introduced in the transgenic heart by breeding with previously established Mer‐Cre‐Mer transgenic mice. Upon tamoxifen administration in double transgenic adult animals, cre‐loxP‐mediated DNA recombination efficiently switches “off” the loxP‐flanked GFP expression unit in cardiomyocytes and switches “on” the expression of the target gene, MKK7D, a constitutively activated upstream activator of c‐Jun N‐terminal kinases (JNK). Expression of MKK7D in adult hearts resulted in significant activation of JNK activities and causes progressive cardiomyopathy in transgenic animals. This unique animal model of cardiac‐specific and temporally regulated JNK activation will provide a powerful tool to investigate the functional role of the JNK pathway in the development of heart failure. Our data also demonstrated that the inducible gene‐switch approach reported here may also be applicable in other studies to achieve efficient, tissue‐specific, and temporally regulated genetic manipulation in intact animals.

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