The MEF2 Transcription Factor is an Essential Regulator of Bone Development

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2006-08-15

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Arnold, Michael Andrew

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Abstract

MEF2 transcription factors are essential regulators of muscle and cardiovascular development. Mice lacking Mef2c die during early embryogenesis due to cardiovascular abnormalities. Using a conditional Mef2c null allele, I show that MEF2C plays an essential and unexpected role in the development of both neural crest derived and mesoderm derived bones. Deletion of MEF2C from the cartilaginous precursors of endochondral bones causes a delay in chondrocyte maturation, resulting in persistent endochondral cartilage, decreased bone growth and short stature. Further, transgenic over expression of a dominant negative or constitutively active MEF2C causes a block in chondrocyte hypertrophy or premature ossification, respectively. HDAC4, a known repressor of MEF2 proteins, inhibits chondrocyte maturation by repressing the Runx2 transcription factor. Intercrosses of the null alleles of Mef2c and HDAC4 reveal that the dynamics of chondrocyte hypertrophy in the endochondral growth plate is controlled by a balance between the positive transcriptional effects of MEF2C against the repressive activity of HDAC4. Misregulation of signaling pathways that influence growth plate dynamics results in dwarfisms and bone deformations due to either accelerated maturation of the growth plate cartilage, characteristic of achondroplasia, or delayed or absent chondrocyte maturation, characteristic of many chondrodysplasia syndromes. MEF2C is capable of directly activating the promoter of collagen a1(X), which marks hypertrophic chondrocytes. I therefore conclude that the association of HDAC4 with MEF2C serves as a switch to directly control gene expression in hypertrophic endochondral cartilage, and therefore the interaction of HDAC4 and MEF2C in chondrocytes may be an opportunity for pharmacologic intervention in disorders of growth plate maturation.

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