MEF2C Transcription Factor Controls Chondrocyte Hypertrophy and Bone Development

• Published in: Developmental cell Vol. 12; no. 3; pp. 377 - 389
• Main Authors: Arnold, Michael A., Kim, Yuri, Czubryt, Michael P., Phan, Dillon, McAnally, John, Qi, Xiaoxia, Shelton, John M., Richardson, James A., Bassel-Duby, Rhonda, Olson, Eric N.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 01.03.2007; Cell Press
• Subjects: Animals; Biological and medical sciences; Bone and Bones - cytology; Bone and Bones - embryology; Bone and Bones - metabolism; Bone Development - genetics; Cartilage - cytology; Cartilage - embryology; Cartilage - metabolism; Cell Differentiation - genetics; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cercopithecus aethiops; Chondrocytes - cytology; Chondrocytes - metabolism; COS Cells; DEVBIO; Dwarfism - genetics; Dwarfism - metabolism; Dwarfism - physiopathology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - genetics; Histone Deacetylases - genetics; Hypertrophy - genetics; Hypertrophy - metabolism; Male; MEF2 Transcription Factors; Mice; Mice, Transgenic; Molecular and cellular biology; Mutation - genetics; Myogenic Regulatory Factors - genetics; Myogenic Regulatory Factors - metabolism; Neovascularization, Physiologic - genetics; Osteogenesis - genetics; DEVBIO; Osteoarticular system; Development; Regulation(control); Bone; Transcription factor; Hypertrophy
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2007.02.004

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.