Core-binding factor β interacts with Runx2 and is required for skeletal development
Core-binding factor β interacts with Runx2 and is required for skeletal development
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DOI：
10.1038/ng1015
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发表时间：
2002-11
期刊：
影响因子：
30.8
通讯作者：
C. Yoshida;T. Furuichi;T. Fujita;R. Fukuyama;Naoko Kanatani;Shinji Kobayashi;M. Satake;K. Takada
中科院分区：
文献类型：
--
作者：
C. Yoshida;T. Furuichi;T. Fujita;R. Fukuyama;Naoko Kanatani;Shinji Kobayashi;M. Satake;K. Takada
核心结合因子β （CBFβ，也称为多瘤病毒增强子结合蛋白2β (PEBP2B)）与16号染色体反转有关，并与人类急性髓性白血病有关1。CBFβ与RUNX1 （runt相关转录因子1）形成异源二聚体，RUNX1具有与果蝇配对规则蛋白runt同源的DNA结合域。RUNX1和CBFβ都是造血2,3,4,5,6所必需的。另一种矮子相关蛋白RUNX2（也称为CBFA1）的单倍体不足会导致人类锁骨颅内发育不良7，并通过调节成骨细胞分化和软骨细胞成熟8,9,10,11,12,13,14,15，在骨骼发育中起重要作用。缺乏Cbfb （Cbfb - / -）的小鼠在妊娠中期死亡4,5,6，因此Cbfb β在骨骼发育中的功能尚未确定。为了研究这一问题，我们通过使用Gata1启动子引入Cbfb来挽救Cbfb - / -小鼠的造血功能。获救的Cbfb - / -小鼠在红细胞和巨核细胞谱系中再现了胎儿肝脏造血功能，并存活到出生，但表现出严重的骨形成延迟。虽然间充质细胞分化为未成熟的成骨细胞，但膜内骨形成不良。软骨细胞向肥大细胞的成熟明显延迟，软骨内骨未形成。电泳迁移率和报告基因分析表明，Cbfβ对于Runx2的有效DNA结合和Runx2依赖性转录激活是必需的。这些发现表明Cbfβ是Runx2在骨骼发育中的功能所必需的。
Core-binding factor β (CBFβ, also called polyomavirus enhancer binding protein 2β (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans 1. CBFβ forms a heterodimer with RUNX1 (runt-related transcription factor 1), which has a DNA binding domain homologous to the pair-rule protein runt in Drosophila melanogaster. Both RUNX1 and CBFβ are essential for hematopoiesis 2, 3, 4, 5, 6. Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans 7 and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation 8, 9, 10, 11, 12, 13, 14, 15. Mice deficient in Cbfb (Cbfb−/−) die at midgestation 4, 5, 6, so the function of Cbfβ in skeletal development has yet to be ascertained. To investigate this issue, we rescued hematopoiesis of Cbfb−/− mice by introducing Cbfb using the Gata1 promoter. The rescued Cbfb−/− mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation. Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. The maturation of chondrocytes into hypertrophic cells was markedly delayed, and no endochondral bones were formed. Electrophoretic mobility shift assays and reporter assays showed that Cbfβ was necessary for the efficient DNA binding of Runx2 and for Runx2-dependent transcriptional activation. These findings indicate that Cbfβ is required for the function of Runx2 in skeletal development.