MEF2C transcription factor controls chondrocyte hypertrophy and bone development
MEF2C transcription factor controls chondrocyte hypertrophy and bone development
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DOI：
10.1016/j.devcel.2007.02.004
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发表时间：
2007-03-01
影响因子：
11.8
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
--
作者：
Arnold, Michael A.;Kim, Yuri;Olson, Eric N.
软骨细胞肥大是软骨内骨发育所必需的。出乎意料的是，我们发现MEF2C，一种调节肌肉和心血管发育的转录因子，通过激活软骨细胞肥大的基因程序来控制骨发育。Mef2c基因缺失或显性阴性MEF2C突变体在软骨内软骨中的表达损害小鼠肥大、软骨血管生成、骨化和纵向骨生长。相反，MEF2C的超活化形式导致早熟软骨细胞肥大、生长板骨化和侏儒症。软骨内骨形成对MEF2C和辅阻遏物组蛋白脱乙酰酶4（HDAC 4）之间的平衡非常敏感，因此Mef2c突变小鼠的骨缺陷可以通过Hdac 4突变来挽救，Hdac 4缺失小鼠的异位骨化可以通过杂合Mef2c突变来减少。这些发现揭示了在MEF2和II类HDAC调节肌肉、心血管和骨骼发育的机制中意想不到的共性。
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.