Disease relevance of Scx

• Murine sclerodermatous graft-vs-host disease (Scl GVHD) models human scleroderma, with prominent skin thickening, lung fibrosis, and up-regulation of cutaneous collagen mRNA [1].

High impact information on Scx

• Scleraxis (Scx), a bHLH transcription factor, marks this somitic tendon progenitor population at its inception, and is continuously expressed through differentiation into the mature tendons [2].
• The transcription factor, Scl/Tal1 (stem cell leukemia protein), is essential for hematopoiesis but thought to be required only for remodeling of endothelium in mouse embryos [3].
• Dual role of the basic helix-loop-helix transcription factor scleraxis in mesoderm formation and chondrogenesis during mouse embryogenesis [4].
• To investigate its function in embryonic development, we produced scleraxis-null mice by gene targeting [4].
• Scleraxis-null cells were specifically excluded from the sclerotomal compartment of somites, which gives rise to the axial skeleton, and from developing ribs, but were able to contribute to most other regions of the embryo, including mesoderm-derived tissues [4].

Biological context of Scx

• The sequential expression of paraxis and scleraxis in the paraxial mesoderm and somites suggests that these bHLH proteins may comprise part of a regulatory pathway involved in patterning of the paraxial mesoderm and in the establishment of somitic cell lineages [5].
• These observations revealed the presence of temporal and spatial association of scleraxis expression during embryonic development of tendon precursor cells in close association with that of Sox9 expression in chondrogenic cells in skeletal tissues [6].
• Subsequently, scleraxis was expressed at high levels within mesenchymal precursors of the axial and appendicular skeleton and in cranial mesenchyme in advance of chondrogenesis; its expression pattern in these cell types foreshadowed the developing skeleton [7].
• Consistent with this early embryonic phenotype, scleraxis was found to be expressed throughout the embryo at the time of gastrulation before becoming restricted to chondrogenic precursor cells at embryonic day 9 [4].
• Scleraxis bound the E-box consensus sequence as a heterodimer with E12 and activated transcription of a reporter gene linked to its DNA-binding site [7].

Anatomical context of Scx

• In contrast to previous reports, we found that this non-myogenic domain is distinct from tendon primordia and from tendons defined by scleraxis expression [8].
• Recently, we cloned a novel basic helix-loop-helix (bHLH) protein, called scleraxis, which is expressed in the sclerotome, in mesenchymal precursors of bone and cartilage, and in connective tissues [5].
• By generating chimeric embryos, using lacZ-marked scleraxis-null and wild-type embryonic stem cells, we examined the ability of mutant cells to contribute to regions of the embryo beyond the time of lethality of homozygous mutants [4].
• Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments [9].
• During mouse embryogenesis, scleraxis transcripts were first detected between day 9.5 and 10.5 post coitum (p.c.) in the sclerotome of the somites and in mesenchymal cells in the body wall and limb buds [7].

Associations of Scx with chemical compounds

• In a domain swapping experiment, we show that integrin binds to the collagenous domain of the Scl protein [10].
• Our results demonstrate a crucial role for Scl in the development of Scl-expressing neurons, including gamma-aminobutyric acid (GABA)ergic interneurons [11].

Physical interactions of Scx

• Paraxis is able to bind to a set of E-boxes that overlaps with the closely related scleraxis [12].

Regulatory relationships of Scx

• At 11.5 d.p.c., scleraxis transcripts were observed in the mesenchymal tissue surrounding skeletal primordia which express Sox9 [6].
• Scleraxis messenger ribonucleic acid is expressed in C2C12 myoblasts and its level is down-regulated by bone morphogenetic protein-2 (BMP2) [13].

Other interactions of Scx

• Moreover, the expression of scleraxis is not affected in early Six1-/- mutant limbs [8].
• Here we report the cloning of a bHLH protein, called paraxis, which is nearly identical to scleraxis within the bHLH region but diverges in its amino and carboxyl termini [5].
• Scleraxis mRNA level was reduced by CDMP treatment [14].
• Scleraxis: a basic helix-loop-helix protein that prefigures skeletal formation during mouse embryogenesis [7].

Analytical, diagnostic and therapeutic context of Scx

• At 4 weeks, MDF( E6-EGFP ) cell transplants had the capacity to generate a PDL-like tissue that expressed periostin, Scx, and type XII collagen and the fibrillar assembly of type I collagen [15].
• We have determined that tendon is first clearly present in mouse limb at embryonic day 14.5 (E14.5) and, by in situ hybridization, that scleraxis is expressed in the mouse tendons at E14 [16].
• Donor cells infiltrating skin in Scl GVHD increase significantly at early time points post-transplantation and are detectable by PCR analysis of Y-chromosome sequences when female mice are transplanted with male cells [1].
• Electrophoresis mobility shift assay showed that the proteins in the crude nuclear extracts prepared from C2C12 cells bound to an Scx-E-box sequence, CATGTG, which is preferentially recognized by scleraxis [13].

References