MEF2C transcription factor controls chondrocyte hypertrophy and bone development.
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.
Arnold
Michael A
MA
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Kim
Yuri
Y
Czubryt
Michael P
MP
Phan
Dillon
D
McAnally
John
J
Qi
Xiaoxia
X
Shelton
John M
JM
Richardson
James A
JA
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
D000818:Animals; D001846:Bone Development / Q000235:genetics*; D001842:Bone and Bones / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D019556:COS Cells; D002356:Cartilage / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002522:Chlorocebus aethiops; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics
D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases