Abstract
Tenascin-C (TNC) is an extracellular matrix glycoprotein that is expressed during embryogenesis. It is not expressed in normal adults, but is up-regulated under pathological conditions. Although TNC knockout mice do not show a distinct phenotype, analyses of disease models using TNC knockout mice combined with in vitro experiments revealed the diverse functions of TNC. Since high TNC levels often predict a poor prognosis in various clinical settings, we developed a transgenic mouse that overexpresses TNC through Cre recombinase-mediated activation. Genomic walking showed that the transgene was integrated into and truncated the Atp8a2 gene. While homozygous transgenic mice showed a severe neurological phenotype, heterozygous mice were viable, fertile, and did not exhibit any distinct abnormalities. Breeding hemizygous mice with Nkx2.5 promoter-Cre or α-myosin heavy chain promoter Cre mice induced the heart-specific overexpression of TNC in embryos and adults. TNC-overexpressing mouse hearts did not have distinct histological or functional abnormalities. However, the expression of proinflammatory cytokines/chemokines was significantly up-regulated and mortality rates during the acute stage after myocardial infarction were significantly higher than those of the controls. Our novel transgenic mouse may be applied to investigations on the role of TNC overexpression in vivo in various tissue/organ pathologies using different Cre donors.
Highlights
Tenascin-C (TNC) is a large extracellular matrix (ECM) glycoprotein and an original member of ‘matricellular proteins’ together with thrombosondin-1 (TSP1) and SPARC [1]
Several truncated forms of the gene product of Atp8a2 were detected by a 3′ rapid amplification of cDNA ends (3′ RACE) analysis
Despite supplementation of dry food with a soft moist diet that was placed on the cage floor to allow easy access, all homo-mutant mice died by 100 days
Summary
Tenascin-C (TNC) is a large extracellular matrix (ECM) glycoprotein and an original member of ‘matricellular proteins’ together with thrombosondin-1 (TSP1) and SPARC (secreted protein acidic and rich in cysteine; osteonectin) [1]. Matricellular proteins are a growing family of unique ECM proteins that do not directly contribute to the formation of structural elements and are strongly up-regulated and modulate cellular functions during tissue remodeling under normal and pathological conditions [2,3,4,5]. As a typical matricellular protein, TNC is transiently expressed at Tenascin-C Overexpressing Mice several steps during embryogenesis, is weakly expressed in normal adults, and is up-regulated under pathological conditions. Disease models using TNC knockout mice revealed its important roles in tissue repair after injury, inflammation and cancer invasion [10,11,12,13,14,15,16]. Accumulating evidence suggests that TNC has diverse functions and may exert harmful and beneficial effects on tissue repair in a context-dependent manner
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