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Presenting Author(s) Brent Edward Bobick
Abstract Title The MEK-ERK kinase cascade negatively regulates chondrogenesis in embryonic limb mesenchyme.
Full author List Brent E. Bobick and William M. Kulyk
Text of abstract

The ERK mitogen-activated protein kinase pathway has recently been implicated in the regulation of embryonic cartilage differentiation, however its precise role remains controversial. To clarify the function of MEK-ERK signaling in limb chondrogenesis, we analyzed the effects of two pharmacological inhibitors of MEK, the upstream kinase activator of ERK, on chondrocyte differentiation in micromass cultures prepared from chick embryo wing bud cells. We found that both MEK inhibitors, U0126 and PD98059, promote increased accumulation of mRNA transcripts for the chondrogenic marker genes, sox9, col2a1, and aggrecan. PD98059 treatment stimulated increased deposition of sulfated glycosaminoglycan (GAG) into both Alcian blue-stainable cartilage matrix and the surrounding culture medium, whereas U0126 treatment elevated GAG secretion into the medium fraction alone.

Both MEK inhibitors increased type II collagen production in micromass culture and elevated the activity of a transfected col2a1 enhancer-luciferase reporter gene. Thus, pharmacological MEK inhibition induced increased expression of multiple chondrocyte differentiation markers. In contrast, when limb mesenchyme cultures were transfected with a plasmid encoding constitutively active MEK, there was a prominent decrease in col2a1-luciferase reporter activity. Collectively, our findings indicate that the MEK-ERK kinase cascade functions as an inhibitory regulator of chondrocyte differentiation in prechondrogenic limb bud mesenchyme. Interestingly, recent investigations in our lab suggest that MEK-ERK signaling might instead act as a positive modulator of chondrogenic differentiation in the neural crest-derived ectomesenchyme of the embryonic mandibular process.

Which session is your work most relevant to: Tissue differentiation