N‐cadherin mediated distribution of β‐catenin alters MAP kinase and BMP‐2 signaling on chondrogenesis‐related gene expression

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Abstract
We have examined the effect of calcium‐dependent adhesion, mediated by N‐cadherin, on cell signaling during chondrogenesis of multipotential embryonic mouse C3H10T1/2 cells. The activity of chondrogenic genes, type II collagen, aggrecan, and Sox9 were examined in monolayer (non‐chondrogenic), and micromass (chondrogenic) cultures of parental C3H10T1/2 cells and altered C3H10T1/2 cell lines that express a dominant negative form of N‐cadherin (Δ390‐T1/2) or overexpress normal N‐cadherin (MNCD2‐T1/2). Our findings show that missexpression or inhibition of N‐cadherin in C3H10T1/2 cells results in temporal and spatial changes in expression of the chondrogenic genes Sox9, aggrecan, and collagen type II. We have also analyzed activity of the serum response factor (SRF), a nuclear target of MAP kinase signaling implicated in chondrogenesis. In semi‐confluent monolayer cultures (minimum cell–cell contact) of C3H10T1/2, MNCD2‐T1/2, or Δ390‐T1/2 cells, there was no significant change in the pattern of MAP kinase or bone morphogenetic protein‐2 (BMP‐2) regulation of SRF. However, in micromass cultures, the effect of MAP kinase and BMP‐2 on SRF activity was proportional to the nuclear localization of β‐catenin, a Wnt stabilized cytoplasmic factor that can associate with lymphoid enhancer‐binding factor (LEF) to serve as a transcription factor. Our findings suggest that the extent of adherens junction formation mediated by N‐cadherin can modulate the potential Wnt‐induced nuclear activity of β‐catenin. Published 2005 Wiley‐Liss, Inc.