MEF2C transcription factor controls chondrocyte hypertrophy and bone development.

Full 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.

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Author information

Author/s: Arnold, Michael A (MA); 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);

Affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Grants: GM08014 (Agency:NIGMS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Developmental cell (Dev Cell), published in United States. (Language: eng)

Reference: 2007-Mar; vol 12 (issue 3) : pp 377-89

Dates: Created 2007/03/05; Completed 2007/04/27; Revised 2007/12/03;

PMID: 17336904, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Bone Development - genetics
Bone and Bones - cytology; embryology; metabolism
COS Cells
Cartilage - cytology; embryology; metabolism
Cell Differentiation - genetics
Cercopithecus aethiops
Chondrocytes - cytology; metabolism
Dwarfism - genetics; metabolism; physiopathology
Female

Gene Expression Regulation, Developmental - genetics
Histone Deacetylases - genetics
Hypertrophy - genetics; metabolism
Male
Mice
Mice, Transgenic
Mutation - genetics
Myogenic Regulatory Factors - genetics; metabolism
Neovascularization, Physiologic - genetics
Osteogenesis - genetics

Associated Chemicals: Mef2c protein, mouse (0) ; Myogenic Regulatory Factors (0) ; Hdac5 protein, mouse (EC 3.5.1.-) ; Histone Deacetylases (EC 3.5.1.-)

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