A twist code determines the onset of osteoblast differentiation
A twist code determines the onset of osteoblast differentiation
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DOI：
10.1016/s1534-5807(04)00058-9
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发表时间：
2004-03-01
影响因子：
11.8
通讯作者：
Karsenty, G
中科院分区：
文献类型：
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作者：
Bialek, P;Kern, B;Karsenty, G
Runx 2是成骨细胞分化所必需和充分的，但其表达先于成骨细胞出现4天。在这里，我们发现Twist蛋白在骨骼发生过程中瞬时抑制Runx 2功能。Twist-1和Twist-2在发育早期在整个骨骼的Runx 2表达细胞中表达，成骨细胞特异性基因表达仅在其表达降低后发生。Twist-1和Runx 2缺失的双杂合子没有在Runx 2（+/-）小鼠中观察到的颅骨异常，Twist-2无效背景挽救了Runx 2（+/-）小鼠的锁骨表型，并且Twist-1或-2缺陷导致过早的成骨细胞分化。此外，Twist-1过表达抑制成骨细胞分化而不影响Runx 2表达。Twist蛋白的抗成骨功能是由一个新的结构域Twist box介导的，该结构域与Runx 2 DNA结合结构域相互作用以抑制其功能。体内诱变证实了Twist box的抗成骨功能。因此，Twist蛋白抑制的缓解是排除成骨细胞分化的强制性事件。
Runx2 is necessary and sufficient for osteoblast differentiation, yet its expression precedes the appearance of osteoblasts by 4 days. Here we show that Twist proteins transiently inhibit Runx2 function during skeletogenesis. Twist-1 and -2 are expressed in Runx2-expressing cells throughout the skeleton early during development, and osteoblast-specific gene expression occurs only after their expression decreases. Double heterozygotes for Twist-1 and Runx2 deletion have none of the skull abnormalities observed in Runx2(+/-) mice, a Twist-2 null background rescues the clavicle phenotype of Runx2(+/-) mice, and Twist-1 or -2 deficiency leads to premature osteoblast differentiation. Furthermore, Twist-1 overexpression inhibits osteoblast differentiation without affecting Runx2 expression. Twist proteins' antiosteogenic function is mediated by a novel domain, the Twist box, which interacts with the Runx2 DNA binding domain to inhibit its function. In vivo mutagenesis confirms the antiosteogenic function of the Twist box. Thus, relief of inhibition by Twist proteins is a mandatory event precluding osteoblast differentiation.