A new model mouse for Duchenne muscular dystrophy produced by 2.4 Mb deletion of dystrophin gene using Cre-loxP recombination system.
Duchenne muscular dystrophy (DMD) is caused by mutation in the 2.4-Mb dystrophin (DMD) gene . This gene encodes a number of tissue-specific isoforms of dystrophin generated by transcription from at least seven promoters and also by alternative splicing. We deleted entire genomic region of the DMD gene on mouse chromosome X using a Cre-loxP recombination system. Introduction of a loxP site in dystrophin's first and last exon by homologous recombination in mouse embryonic stem (ES) cells generated "DMD-floxed" (flanked by loxP sites) ES cells, which we subjected to Cre-mediated excision leading to establishment of "DMD-null" ES cell lines. The DMD-null mice produced from the DMD-null ES cells were viable but displayed severe muscular hypertrophy and dystrophy. In addition to the muscular impairment, the DMD-null mouse exhibited some behavioral abnormality and male sterility. The DMD-floxed mice produced from the DMD-floxed ES cells were viable, phenotypically normal, and were born with the expected Mendelian frequency, despite the absence of brain (cortical)-type dystrophin (Dp427c) expression. Since production of multiple dystrophin isoforms due to alternative splicing or exon skipping is totally prevented in the DMD-null mouse, these new mutants will provide an improved model system for functional studies of dystrophin and its isoforms.
Kudoh
Hiroe
H
Laboratory of Molecular Embryology, Department of Bioscience, Kitasato University School of Science, Sagamihara, Kanagawa 228-8555, Japan.
Ikeda
Haruko
H
Kakitani
Makoto
M
Ueda
Akiko
A
Hayasaka
Michiko
M
Tomizuka
Kazuma
K
Hanaoka
Kazunori
K
D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics*; D017353:Gene Deletion; D018390:Gene Targeting / Q000379:methods*; D005818:Genetic Engineering / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D020388:Muscular Dystrophy, Duchenne / Q000175:diagnosis* / Q000235:genetics*; D016297:Mutagenesis, Site-Directed / Q000235:genetics
D016189:Dystrophin