Research on Gene Expression Network via Coactivator CBP

人类CBP基因突变似乎与Rubinstein-Taybi综合征（RTS）有关，这是一种以异常模式形成为特征的单倍体功能不全疾病。然而，CBP水平降低影响模式形成的机制尚不清楚。hedgehog （hh）信号通路是模式形成的重要决定因素。cubitus interruptus （ci）是hh信号的一个组成部分，编码一种与Gli蛋白家族同源的转录因子，是诱导斑块（ptc）、decapentaplegic （dpp）和无翼（wg） hh依赖性表达所必需的。有趣的是，ci相关转录因子Gli3的单倍不足会导致小鼠（称为“额外脚趾”）和人类（格雷格头多并指综合征）的表型变化，这与RTS有相似之处。我们的分子和遗传学研究表明，果蝇CBP （dCBP）作为Ci的共激活剂起作用。因此，dbp - ci相互作用可能为理解CBP对哺乳动物模式形成的贡献提供线索。此外，我们发现dCBP突变体不能表达扭曲（twi）基因并产生扭曲胚胎。结果表明，dCBP是dl介导的twin基因启动子激活所必需的。此外，我们发现，在杂合cbp缺陷小鼠的骨骼系统中，由于C57BL/6-CBA与BALB/c杂交，各种异常发生的频率很高。为了支持昆虫和哺乳动物模式形成的保守信号通路，在杂合突变体中发现Bmp7的表达减少。

Mutations in the human CBP gene appear to be associated with the Rubinstein-Taybi syndrome (RTS), a haploinsufficiency disorder characterized by abnormal pattern formation. However, the mechanism by which decreased CBP levels affect pattern formation is unclear. The hedgehog (hh) signaling pathway is an important determinant of pattern formation. cubitus interruptus (ci), a component of hh signaling, encodes a transcription factor homologous to the Gli family of proteins, and is required for induction of the hh-dependent expression of patched (ptc), decapentaplegic (dpp) and wingless (wg). Interestingly, a haploinsufficiency for the ci-related transcription factor Gli3 causes phenotypic changes in mice (known as "extra-toes") and humans (Greig's cephalopolysyndactyly syndrome) that have similarities to RTS.Our molecular and genetic studies indicated that Drosophila CBP (dCBP) functions as a co-activator of Ci. Thus, the dCBP-Ci interaction may provide clues for understanding the contribution of CBP to pattern formation in mammals. In addition, we showed that dCBP mutants fail to express the twist (twi) gene and generate twisted embryo. This is explained by results showing that dCBP is necessary for dl-mediated activation of the twi gene promoter. Furthermore, We showed that various abnormalities occur at high frequency in the skeletal system of heterozygous Cbp-deficient mice resulting from a C57BL/6-CBA x BALB/c cross. In support of a conserved signaling pathway for pattern formation in insects and mammals, the expression of Bmp7 was found to be reduced in the heterozygous mutants.