Disease relevance of Spg3a

• De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy [1].
• BACKGROUND: Mutations in the SPG3A gene (atlastin protein) cause approximately 10% of autosomal-dominant hereditary spastic paraplegia [1].
• This pattern of anti-FSP1 staining during tissue fibrosis suggests, as a hypothesis, that fibroblasts in some cases arise, as needed, from the local conversion of epithelium [2].
• More frequent lung metastases were observed in naïve recipients given purified populations of green fluorescent protein (GFP)(+) tumor cells harvested from PyV-mT x FSP1(+/+.GFP) F1 mice compared with GFP(-) tumor cells (P < or = 0.01), where GFP expression is under the control of the FSP1 promoter [3].

High impact information on Spg3a

• While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1) [4].
• A small number of FSP1(+), CD34(-) fibroblasts migrate to normal interstitial spaces from bone marrow [4].
• Similarly, tubular epithelium submerged in type I collagen gels exhibited the conversion to a fibroblast phenotype which includes de novo expression of FSP1 and vimentin [2].
• Polyclonal antiserum raised to recombinant FSP1 protein stained the cytoplasm of fibroblasts, but not epithelium [2].
• With the recent description of fibroblast-specific protein 1 (FSP1), we revisited the specificity of antibodies directed against macrophages to determine systematically which antibodies best distinguish both cell types in fibrotic tissues [5].

Biological context of Spg3a

• During development, FSP1 is first detected by in situ hybridization after day 8.5 as a postgastrulation event, and is associated with cells of mesenchymal origin or of fibroblastic phenotype [2].
• METHODS: Tissue fibrosis was produced in mice carrying the GFP transgene encoding green fluorescent protein under the control of the FSP1 promoter [5].
• The FSP1 gene encodes a filament-binding S100 protein with paired EF hands that is specifically expressed in fibroblasts [6].
• To confirm that it was the induction of Fsp1 by these cytokines mediating EMT, we used antisense oligomers to block Fsp1 production and subsequently measured cell motility and markers of EMT phenotype [7].

Anatomical context of Spg3a

• RESULTS: Mice receiving peritoneal infusions of CHG saline every other day for 2 weeks developed increasing numbers of FSP1+ fibroblasts in the subserosal layers of the visceral peritoneum [8].
• Some FSP1+ fibroblasts are likely derived from tubular epithelium undergoing EMT, while alphaSMA+, VIM- cells probably represent vascular smooth muscle cells or pericytes surviving vessel attenuation during the chaos of fibrogenesis [9].
• In the current study, we identified several cytokines that induce Fsp1 in cultured epithelial cells [7].
• We review the genes, such as FSP1, src, ras, and fos, that are activated in cells transforming to mesenchyme and the genes their neighbors activate to induce EMT, such as those for TGF beta, NT-3, and sonic hedgehog [10].

References