Horan G S, Ramírez-Solis R, Featherstone M S, Wolgemuth D J, Bradley A, Behringer R R
Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Genes Dev. 1995 Jul 1;9(13):1667-77. doi: 10.1101/gad.9.13.1667.
The Hox gene products are transcription factors involved in specifying regional identity along the anteroposterior body axis. In the mouse, several single mutants for Hox genes show variably penetrant, partial homeotic transformations of vertebrae at their anterior limits of expression, suggesting that compound Hox mutants might show more complete transformations with greater penetrance than the single Hox mutants. Compound mutants for the paralogous group 3 genes, hoxa-3 and hoxd-3, show deletion of a cervical vertebrae, which is not readily interpretable in terms of an alteration in regional identity. Here, we report the skeletal phenotypes of compound mutants in the group 4 Hox genes, hoxa-4, hoxb-4, and hoxd-4. Mice mutant for each of these genes were intercrossed to generate the three possible double mutant combinations and the triple mutant. In contrast to the hoxa-3, hoxd-3 double mutants, group 4 Hox compound mutants displayed clear alterations in regional identity, including a nearly complete transformation of the second cervical vertebrae toward the morphology of the first cervical vertebra in one double mutant combination. In comparing the types of homeotic transformations observed, different double mutant combinations showed different degrees of synergism. These results suggest a certain degree of functional redundancy among paralogous genes in specifying regional identity. Furthermore, there was a remarkable dose-dependent increase in the number of vertebrae transformed to a first cervical vertebra identity, including the second through the fifth cervical vertebrae in the triple mutant. Thus, these genes are required in a larger anteroposterior domain than is revealed by the single mutant phenotypes alone, such that multiple mutations in these genes result in transformations of vertebrae that are not at their anterior limit of expression.
Hox基因产物是参与沿前后体轴确定区域特征的转录因子。在小鼠中，几种Hox基因的单突变体在其表达的前边界显示出可变的、部分同源异型的椎骨转化，这表明复合Hox突变体可能比单Hox突变体表现出更完全的转化且具有更高的外显率。同源异型群3基因hoxa - 3和hoxd - 3的复合突变体显示出一个颈椎的缺失，这难以用区域特征的改变来解释。在此，我们报告了第4组Hox基因hoxa - 4、hoxb - 4和hoxd - 4复合突变体的骨骼表型。将这些基因各自的突变小鼠进行杂交，以产生三种可能的双突变组合和三突变体。与hoxa - 3、hoxd - 3双突变体不同，第4组Hox复合突变体在区域特征上表现出明显改变，包括在一种双突变组合中第二颈椎几乎完全向第一颈椎形态转化。在比较所观察到的同源异型转化类型时，不同的双突变组合表现出不同程度的协同作用。这些结果表明在确定区域特征方面同源基因之间存在一定程度的功能冗余。此外，转化为第一颈椎特征的椎骨数量有显著的剂量依赖性增加，包括三突变体中第二至第五颈椎。因此，这些基因在比单独单突变体表型所揭示的更大的前后区域中是必需的，以至于这些基因的多个突变会导致不在其表达前边界的椎骨转化。
