Disease relevance of Tsk2

• These findings are similar to those described for fibroblasts from humans with systemic sclerosis and validate the use of Tsk2 as a model for the study of the connective tissue alterations in this disease [1].
• The tight skin 2 mouse. An animal model of scleroderma displaying cutaneous fibrosis and mononuclear cell infiltration [2].

High impact information on Tsk2

• The Tsk2/+ mouse also has been reported to have a mononuclear cell infiltrate in the dermis; however, to date no evidence of autoimmunity has been described in this animal model [3].
• However, the Tsk2/+ mice also develop autoantibodies to dsDNA and a majority of the mice develop multiple autoantibody specificities (anti-Scl70, anti-CENP-B, and anti-dsDNA) indicating that the mouse may be a useful model to study autoimmunity in a wider spectrum of connective tissue diseases [3].
• The tight skin-2 (Tsk2/+) mouse has been proposed as an animal model of systemic sclerosis (SSc) because this animal exhibits increased collagen synthesis and accumulation in the dermis [3].
• Lack of endothelial cell apoptosis in the dermis of tight skin 1 and tight skin 2 mice [4].
• Up-regulation of mRNA for 2 extracellular matrix proteins was observed in the Tsk2 dermal fibroblasts compared with the normal cells: the alpha1(I) procollagen mRNA steady-state levels were 50% higher, and those of the alpha1(III) procollagen mRNA 100% higher, in Tsk2 cells [1].

Biological context of Tsk2

• CONCLUSION: Dermal fibroblasts from Tsk2 mice display increased collagen synthesis and up-regulation of alpha1(I) and alpha1(III) procollagen mRNA in vitro [1].
• Electrophoretic mobility shift assays performed with a probe encompassing a relevant COL1A1 promoter region revealed increased DNA-protein binding activities in nuclear extracts prepared from Tsk2 fibroblasts compared with normal fibroblasts [1].
• Transcriptional activation of alpha 1(III) procollagen gene in Tsk2/+ dermal fibroblasts [5].
• Transient transfection experiments into Tsk2/+ and normal dermal fibroblasts were performed using four successively shorter Col3a1 promoter deletion constructs: #103, #110, #114, and #120 fused to the chloramphenicol-acetyl-transferase (CAT) reporter gene [5].
• An intersubspecific backcross was conducted as a first step toward identifying the position of the Tsk2 locus on mouse chromosome 1 [2].

Anatomical context of Tsk2

• METHODS: Dermal fibroblasts from Tsk2 mice and from normal age- and sex-matched control mice were studied [1].
• RESULTS: Histologic examination of Tsk2/+ mouse skin revealed marked accumulation of collagen and infiltration with mononuclear cells in the dermis and adipose tissue [2].
• These data suggest that a restricted T cell population participates in the inflammatory cell infiltrate of Tsk2 skin [6].
• RT-PCR signals were observed in all lymph node cell (LNC) samples from both Tsk2 mice and control mice, with eighteen of the twenty-one Vbeta types present [6].

Physical interactions of Tsk2

• Electrophoretic mobility shift assays with a labeled #120 probe revealed that increased DNA-protein binding occurred with nuclear extracts prepared from Tsk2/+ fibroblasts and that this binding was displaced by consensus Sp1 and NF-1 oligonucleotide sequences [5].

Regulatory relationships of Tsk2

• These data indicate that sequences from -96 to +16bp of the Col3a1 promoter play an important role in the upregulated expression of this gene in Tsk2/+ fibroblasts and that the promoter contains sequences which bind the trans-acting nuclear factors, Sp1(like) and NF-1(like) [5].

Analytical, diagnostic and therapeutic context of Tsk2

• Immunofluorescence with HEp-2 cells revealed the presence of anti-nuclear Abs (ANAs) in the plasma of 92% of the Tsk2/+ mice [3].
• Indirect immunofluorescence with Crithidia luciliae and ELISA for anti-dsDNA Abs showed that 76% of Tsk2/+ mice were positive for this autoantibody [3].

References