SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation
SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation
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DOI：
10.1016/j.cell.2006.05.012
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发表时间：
2006-06-02
期刊：
影响因子：
64.5
通讯作者：
Grosschedl, Rudolf
中科院分区：
文献类型：
--
作者：
Dobreva, Gergana;Chahrour, Maria;Grosschedl, Rudolf
脊椎动物的骨骼发生包括两个过程，骨骼的形成和成骨细胞的分化。在这里，我们表明，Satb 2，编码核基质蛋白，在鳃弓和成骨细胞谱系的细胞中表达。Satb 2（-/-）小鼠表现出类似于在携带SATB 2易位的人类中观察到的颅面异常以及成骨细胞分化和功能缺陷。多个成骨细胞特异性基因被鉴定为受SATB 2正调节的靶点。此外，SATB 2被发现抑制几个Hox基因的表达，包括Hoxa 2，骨形成的抑制剂和鳃弓图案的调节剂。分子分析显示，SATB 2直接与Runx 2和ATF 4相互作用并增强其活性，Runx 2和ATF 4是调节成骨细胞分化的转录因子。Satb 2/Runx 2和Satb 2/Atf 4双杂合小鼠的骨形成缺陷在遗传学上证实了这种协同作用。因此，SATB 2在调节骨骼发育和成骨细胞分化的转录网络中充当分子节点。
Vertebrate skeletogenesis involves two processes, skeletal patterning and osteoblast differentiation. Here, we show that Satb2, encoding a nuclear matrix protein, is expressed in branchial arches and in cells of the osteoblast lineage. Satb2(-/-) mice exhibit both craniofacial abnormalities that resemble those observed in humans carrying a translocation in SATB2 and defects in osteoblast differentiation and function. Multiple osteoblast-specific genes were identified as targets positively regulated by SATB2. In addition, SATB2 was found to repress the expression of several Hox genes including Hoxa2, an inhibitor of bone formation and regulator of branchial arch patterning. Molecular analysis revealed that SATB2 directly interacts with and enhances the activity of both Runx2 and ATF4, transcription factors that regulate osteoblast differentiation. This synergy was genetically confirmed by bone formation defects in Satb2/Runx2 and Satb2/Atf4 double heterozygous mice. Thus, SATB2 acts as a molecular node in a transcriptional network regulating skeletal development and osteoblast differentiation.