The utrophin promoter A drives high expression of the transgenic LacZ gene in liver, testis, colon, submandibular gland, and small intestine

Joji Takahashi, Yuka Itoh, Keita Fujimori, Michihiro Imamura, Yoshihiro Wakayama, Yuko Miyagoe-Suzuki, Shin'ichi Takeda
Journal of Gene Medicine 2005, 7 (2): 237-48

BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by the absence of the muscle cytoskeletal protein dystrophin. Utrophin is an autosomal homologue of dystrophin, and overexpression of the protein is expected to compensate for the defect of dystrophin. The utrophin gene has two promoters, A and B, and promoter A of the utrophin gene is a possible target of pharmacological interventions for DMD because A-utrophin is up-regulated in dystrophin-deficient mdx skeletal and cardiac muscles. To investigate the utrophin promoter A activity in vivo, we generated nuclear localization signal-tagged LacZ transgenic mice, where the LacZ gene was driven by the 5-kb flanking region of the A-utrophin gene.

METHODS: Four transgenic lines were established by mating four independent founders with C57BL/6J mice. The levels of mRNA for beta-galactosidase in several tissues were examined by RT-PCR. Cryosections from several tissues were stained with hematoxylin and eosin (H&E) and with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-Gal).

RESULTS: The 5-kb upstream region of the A-utrophin gene showed high transcriptional activity in liver, testis, colon, submandibular gland, and small intestine, consistent with the endogenous expression of utrophin protein. Surprisingly, the levels of both beta-gal protein and mRNA for the transgene in cardiac and skeletal muscles were extremely low, even in nuclei near the neuromuscular junctions. These results indicate that the regulation of the utrophin gene in striated muscle is different from that in non-muscle tissues.

CONCLUSIONS: Our results clearly showed that the utrophin A promoter is not sufficient to drive expression in muscle, but other regulatory elements are required.

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