Genetic enhancement of limb defects in a mouse model of Cornelia de Lange syndrome.
Genetic enhancement of limb defects in a mouse model of Cornelia de Lange syndrome.
复制标题
DOI：
10.1002/ajmg.c.31491
复制
发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Lander AD
中科院分区：
文献类型：
--
作者：
Lopez-Burks ME;Santos R;Kawauchi S;Calof AL;Lander AD
Cornelia de Lange综合征(CDLS)的特征是身体几乎每个器官系统都有各种各样的结构和功能异常。目前已知CDLS是由扰乱粘连蛋白复合体或其调节因子功能的突变引起的，对动物模型和细胞系的研究告诉我们，这些突变的影响是产生微妙但普遍的基因表达失调。由于在每种细胞类型和组织中都会发生数百种主要是微小的基因表达变化，因此识别任何特定出生缺陷的病因是非常具有挑战性的。在这里，我们集中于肢体异常，这是常见的CDL。在Nipbl单倍体缺陷小鼠(Nipbl+/−小鼠)的肢芽中，观察到几条候选通路的基因表达发生了适度的变化，这些通路被认为是导致肢体异常的原因，而Nipb1+/−小鼠的四肢发育相对正常。我们假设候选通路的进一步损伤可能会产生类似于CDL的肢体缺陷，并进行了基因实验来测试这一点。聚焦于Sonic Hedgehog(Shh)、骨形态发生蛋白(BMP)和Hox基因通路，我们发现BMP或Hox功能降低(但不是Shh功能)会增加Nipb1+/−小鼠的多指，并在某些情况下产生新的骨骼表型。然而，在CDL患者的子集中看到的坦率的肢体减少并没有发生，这表明额外的信号和/或基因调控途径参与了这种戏剧性变化的产生。
Cornelia de Lange Syndrome (CdLS) is characterized by a wide variety of structural and functional abnormalities in almost every organ system of the body. CdLS is now known to be caused by mutations that disrupt the function of the cohesin complex or its regulators, and studies of animal models and cell lines tell us that the effect of these mutations is to produce subtle yet pervasive dysregulation of gene expression. With many hundreds of mostly small gene expression changes occurring in every cell type and tissue, identifying the etiology of any particular birth defect is very challenging. Here we focus on limb abnormalities, which are commonly seen in CdLS. In the limb buds of the Nipbl-haploinsufficient mouse (Nipbl+/− mouse), a model for the most common form of CdLS, modest gene expression changes are observed in several candidate pathways whose disruption is known to cause limb abnormalities, yet the limbs of Nipbl+/− mice develop relatively normally. We hypothesized that further impairment of candidate pathways might produce limb defects similar to those seen in CdLS, and performed genetic experiments to test this. Focusing on Sonic hedgehog (Shh), Bone morphogenetic protein (Bmp), and Hox gene pathways, we show that decreasing Bmp or Hox function (but not Shh function) enhances polydactyly in Nipbl+/− mice, and in some cases produces novel skeletal phenotypes. However, frank limb reductions, as are seen in a subset of individuals with CdLS, do not occur, suggesting that additional signaling and/or gene regulatory pathways are involved in producing such dramatic changes.