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Characterization of a tet‐repressible muscle‐specific Pitx1 transgenic mouse model as an animal model of FSHD
Author(s) -
Dixit Manjusha,
Shi Rongye,
Sutherland Margret,
Munger Stephanie,
Chen YiWen
Publication year - 2007
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/fasebj.21.6.a1148-b
Subject(s) - genetically modified mouse , transgene , facioscapulohumeral muscular dystrophy , biology , muscle atrophy , skeletal muscle , muscular dystrophy , doxycycline , microbiology and biotechnology , homeobox , transcription factor , gene , genetics , endocrinology , antibiotics
Facioscapulohumeral muscular dystrophy (FSHD) is an inherited muscle disorder caused by a deletion of the 3.3 kb D4Z4 array in the subtelomeric region of chromosome 4q35. The only known gene, double homeobox protein 4, in each of the repeat unit was shown to activate paired‐like homeodomain transcription factor 1 (Pitx1) which was specifically up‐regulated in muscles of patients with FSHD. In this study, we hypothesized that up‐regulation of Pitx1 in muscles activated molecular pathways involved in muscle atrophy. Tet‐repressible muscle‐specific Pitx1 transgenic mice were generated by crossing Pitx1 transgenic mice (TRE‐Pitx1) with transgenic mice expressing tetracycline activator driven by mouse creatine kinase promoter (mCK‐tTA). The TRE‐Pitx1/mCK‐tTA mice were kept on doxycycline (200μg/ml) until 3 weeks old. Five weeks after complete withdrawing doxycycline, the mice showed significant weight loss, kyphosis, contracture, reduction of vertical and horizontal movements comparing to single transgenic sibling (tTA). Over‐expression of Pitx1 was confirmed by immunohistochemistry in myonuclei of skeletal muscles, while it was not observed in other tissues. Hematoxylin and Eosin staining showed many angular atrophic myofibers, few necrotic myofibers and mild inflammation infiltration. The results suggested that the gene might play important role in muscle atrophy and in the development of FSHD.