Mouse Snail Family Transcription Repressors Regulate Chondrocyte, Extracellular Matrix, Type II Collagen, and Aggrecan

Abstract

Snail family genes are conserved among species during evolution and encode transcription factors expressed at different stages of development in different tissues. These genes are involved in a broad spectrum of biological functions: cell differentiation, cell motility, cell cycle regulation, and apoptosis. However, little is known about the target genes involved in these functions. Here we show that mouse Snail family members, Snail (Sna) and Slug (Slugh), are involved in chondrocyte differentiation by controlling the expression of type II collagen (Col2a1) and aggrecan. In situ hybridization analysis of developing mouse limb demonstrated that Snail and Slug mRNAs were highly expressed in hypertrophic chondrocytes. Inversely, the expression of collagen type II mRNA disappeared during hypertrophic differentiation. Snail and Slug mRNA expression was down-regulated during differentiation of the mouse chondrogenic cell line ATDC5 and overexpression of exogenous Snail or Slug in ATDC5 cells inhibited expression of collagen type II and aggrecan mRNA. Reporter analysis revealed Snail and Slug suppressed the promoter activity of Col2a1, and the E-boxes in the promoter region were the responsible element. Gel shift assay demonstrated the binding of Snail to the E-box. Because type II collagen and aggrecan are major functional components of extracellular matrix in cartilage, these results suggest an important role for Snailrelated transcription repressors during chondrocyte differentiation.During skeletal development, condensed mesenchymal cells give rise to chondrocytes and form cartilage primordia, which serve as templates for endochondral bone formation. In cartilage primordia, chondrocytes undergo further differentiation, starting as proliferating chondrocytes, becoming prehypertrophic chondrocytes and ending as hypertrophic chondrocytes. Chondrocytes secrete abundant extracellular matrix (ECM) 1 into the extracellular space, and the composition of ECM changes during the sequential differentiation steps. Type II collagen and aggrecan are major components of the cartilage extracellular matrix produced by proliferating and prehypertrophic chondrocytes, and type X collagen is a major collagen type produced by hypertrophic chondrocytes. The differentiation into hypertrophic chondrocytes is accompanied with changes in ECM; switching of collagen types from type II to type X and the disappearance of aggrecan and link protein (1, 2

Transcription factors related to chondrogenesis in pleomorphic adenoma of the salivary gland: a mechanism of mesenchymal tissue formation

“…For cartilage-specific genes, these include δEF1, AP-2α, Snail, Slug, Twist1, and C/EBPβ. [18][19][20][21][22] Among these, δEF1, AP-2α, and Twist1 are expressed by chondrocyte progenitors and maintain their undifferentiated state. 18,20,21,23 Their expression in the salivary gland was therefore compared with their expression in pleomorphic adenoma.…”

“…17 Negative regulators include δEF1, AP-2α, Snail, Slug, Twist1, and C/EBPβ. [18][19][20][21][22] Snail, Slug, and C/EBPβ are expressed by hypertrophic chondrocytes, which indicates that they control terminal chondrocyte differentiation and promote endochondral ossification; 11,19,22 δEF1, AP-2α, and Twist1 are expressed by chondroprogenitors, which indicates that they control early-phase chondrogenesis. 18,20,21,23 The aim of our study was to clarify the mechanisms behind chondrogenesis in pleomorphic adenoma epithelial cells.…”

The zebrafish bcl-2 homologue Nrz controls development during somitogenesis and gastrulation via apoptosis-dependent and -independent mechanisms

“…A number of genes involved in cell-cell or cell-matrix interactions, such as E-cadherin, 27 fibronectin, 18 collagen type II, 28 appear to be regulated by the Snail family of transcription factors. Some of them regulate cell movements during early embryogenesis.…”

Endocellular polyamine availability modulates epithelial-to-mesenchymal transition and unfolded protein response in MDCK cells

“…We substantially confirmed earlier immunohistochemical and electron microscopy findings by Parkkinen et al 38 These authors showed in fact redistribution, whorl formation, and autophagy of the ER in polyamine-deprived BHK cells. This is of particular interest in view of recent in vitro studies 39,40 demonstrating that disturbances of the ER homeostasis results in a EMT-like process characterized by cell morphology changes and extensive reorganization of the actin cytoskeleton. 2,39,40 In our model, endocellular polyamine depletion dramatically enhances TGFb 1 -induced EMT, by increasing at the same time the expression of typical ER-stress proteins like GRP78 and GRP94, thus suggesting a direct involvement of ER-stress in the overall and polyamine depletion-dependent scenario.…”