TY - JOUR
T1 - MEF2C Transcription Factor Controls Chondrocyte Hypertrophy and Bone Development
AU - Arnold, Michael A.
AU - Kim, Yuri
AU - Czubryt, Michael P.
AU - Phan, Dillon
AU - McAnally, John
AU - Qi, Xiaoxia
AU - Shelton, John M.
AU - Richardson, James A.
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
N1 - Funding Information:
We thank J. Brown for editorial assistance, D. Corgan and C. Nolen for technical assistance, and A. Tizenor for graphics. We also thank Dr. R. Behringer for Col2-Cre mice and Dr. D. Vestweber for endomucin antibodies. M.A.A. was supported by the Medical Scientist Training Program at University of Texas Southwestern Medical Center, National Institutes of Health (NIH)-National Institute of General Medical Sciences Grant #GM08014, and the Perot Family Foundation. Work in the laboratory of E.N.O. was supported by grants from the NIH, The Donald W. Reynolds Cardiovascular Clinical Research Center, and the Robert A. Welch Foundation, Grant 1-0025.
PY - 2007/3
Y1 - 2007/3
N2 - 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.
AB - 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.
KW - DEVBIO
UR - http://www.scopus.com/inward/record.url?scp=33847183440&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847183440&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2007.02.004
DO - 10.1016/j.devcel.2007.02.004
M3 - Article
C2 - 17336904
AN - SCOPUS:33847183440
SN - 1534-5807
VL - 12
SP - 377
EP - 389
JO - Developmental cell
JF - Developmental cell
IS - 3
ER -