Dobreva Gergana, Chahrour Maria, Dautzenberg Marcel, Chirivella Laura, Kanzler Benoit, Fariñas Isabel, Karsenty Gerard, Grosschedl Rudolf
Max-Planck Institute of Immunobiology, Department of Cellular and Molecular Immunology, 79108 Freiburg, Germany.
Cell. 2006 Jun 2;125(5):971-86. doi: 10.1016/j.cell.2006.05.012.
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.
脊椎动物骨骼发生涉及两个过程，即骨骼模式形成和成骨细胞分化。在此，我们表明，编码一种核基质蛋白的Satb2在鳃弓和成骨细胞谱系的细胞中表达。Satb2基因敲除小鼠表现出颅面异常，类似于在携带SATB2基因易位的人类中观察到的异常，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SATB2正向调控的靶标。此外，发现SATB2可抑制包括Hoxa2在内的多个Hox基因的表达，Hoxa2是骨形成的抑制剂和鳃弓模式形成的调节因子。分子分析表明，SATB2直接与调节成骨细胞分化的转录因子Runx2和ATF4相互作用并增强其活性。Satb2/Runx2和Satb2/Atf4双杂合小鼠的骨形成缺陷在基因水平上证实了这种协同作用。因此，SATB2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。
