MEF2C transcription factor controls chondrocyte hypertrophy and bone development.

Abstract

Chondrocyte hypertrophy is essential for endochondral bone development. Unexpectedly, we discovered that MEF2C, a transcription factor that regulates muscle and cardiovascular development, controls bone development by activating the gene program for chondrocyte hypertrophy. Genetic deletion of Mef2c or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice. Conversely, a superactivating form of MEF2C causes precocious chondrocyte hypertrophy, ossification of growth plates, and dwarfism. Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4), such that bone deficiency of Mef2c mutant mice can be rescued by an Hdac4 mutation, and ectopic ossification in Hdac4 null mice can be diminished by a heterozygous Mef2c mutation. These findings reveal unexpected commonalities in the mechanisms governing muscle, cardiovascular, and bone development with respect to their regulation by MEF2 and class II HDACs.

• Authors: Michael A Arnold, Yuri Kim, Michael P Czubryt, Dillon Phan, John McAnally, Xiaoxia Qi, John M Shelton, James A Richardson, Rhonda Bassel-Duby, Eric N Olson
• Journal: Developmental cell (Dev Cell) Vol. 12 Issue 3 Pg. 377-89 (Mar 2007) ISSN: 1534-5807 [Print] United States
• PMID: 17336904 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MEF2 Transcription Factors
• Mef2c protein, mouse
• Myogenic Regulatory Factors
• Hdac5 protein, mouse
• Histone Deacetylases

Topics

• Animals
• Bone Development (genetics)
• Bone and Bones (cytology, embryology, metabolism)
• COS Cells
• Cartilage (cytology, embryology, metabolism)
• Cell Differentiation (genetics)
• Chlorocebus aethiops
• Chondrocytes (cytology, metabolism)
• Dwarfism (genetics, metabolism, physiopathology)
• Female
• Gene Expression Regulation, Developmental (genetics)
• Histone Deacetylases (genetics)
• Hypertrophy (genetics, metabolism)
• MEF2 Transcription Factors
• Male
• Mice
• Mice, Transgenic
• Mutation (genetics)
• Myogenic Regulatory Factors (genetics, metabolism)
• Neovascularization, Physiologic (genetics)
• Osteogenesis (genetics)