Abstract
Wnt signaling is essential for many developmental processes, including skeletogenesis. To investigate the effects of Wnt signaling during skeletogenesis we studied the effects of Wnt on cultured chondrocytic cells and differentiating limb-bud mesenchyme. We showed that Wnt3a strongly repressed chondrogenesis and chondrocyte gene expression. Canonical Wnt signaling was responsible for the repression of differentiation, as evidenced by results showing that inhibition of glycogen synthase kinase 3 or expression of beta-catenin caused similar repression of differentiation. Significantly, we showed that the transcription repressor Twist1 is induced by canonical Wnt signaling. Expression of Twist1 strongly inhibited chondrocyte gene expression and short hairpin RNA knockdown of Twist1 transcript levels caused increased expression of the chondrocyte-specific genes aggrecan and type II collagen. Interestingly, Twist1 interfered with BMP2-induced expression of aggrecan and type II collagen expression and knockdown of Twist1 augmented BMP2-induced aggrecan and type II collagen expression. These data support the conclusions that Twist1 contributes to the repression of chondrogenesis and chondrocyte gene expression resulting from canonical Wnt signaling and that Twist1 interferes with BMP-dependent signaling.
Highlights
To better understand the regulation of chondrogenesis by Wnt signaling we investigated early steps of chondrocyte differentiation as determined by the regulation of the cartilage-specific genes aggrecan and type II collagen in the chondrogenic cell line ATDC5
We showed that canonical Wnt signaling induces the transcriptional repressor Twist1 and represses chondrogenesis and chondrocyte gene expression
Our data show that Wnt signaling represses chondrogenesis and chondrocyte gene expression
Summary
The findings indicate that 1) Wnts can both stimulate and inhibit chondrogenesis and 2) overexpression or targeted deletion of cat has similar consequences on chondrocyte differentiation This suggests that Wnt signaling regulates different target genes or proteins depending on the context of the cell or stage of differentiation. Expression of Twist inhibited chondrocyte gene expression following stimulation with BMP2 and shRNA knockdown of Twist augmented chondrocyte gene expression at low concentrations of BMP2 These data support our conclusion that Twist is an important target of Wnt signaling that contributes to the repression of chondrogenesis by canonical Wnt signaling. These data suggest that Twist regulates chondrocyte gene expression through interactions with BMP-dependent pathways
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