ABSENCE OF RADIUS AND ULNA IN MICE LACKING HOXA-11 AND HOXD-11
ABSENCE OF RADIUS AND ULNA IN MICE LACKING HOXA-11 AND HOXD-11
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DOI：
10.1038/375791a0
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发表时间：
1995-06-29
期刊：
影响因子：
64.8
通讯作者：
CAPECCHI, MR
中科院分区：
文献类型：
--
作者：
DAVIS, AP;WITTE, DP;CAPECCHI, MR
已经产生了在Hox基因中具有靶向破坏（1）的小鼠，以评估Hox复合体在决定哺乳动物身体计划中的作用。这个由38个基因组成的复合体编码转录因子，这些转录因子沿着胚胎轴沿着指定区域信息。在脊椎动物进化的早期，与无脊椎动物共有的祖先复合体复制两次，产生四个连锁群（Hox A、B、C和D）（2，3）。因此，在独立的连锁群上的相应基因，称为旁系同源物，彼此之间的关系最为密切。基于序列相似性，Hox基因已被细分为13个旁系同源组。5个最大的5'组（Hox 9-13）图案化脊椎动物胚胎的后部区域和无骨骨骼（4-18）。已经描述了在旁系同源基因hoxa-11和hoxd-11中具有个体突变的小鼠（15-18）。通过将这两种菌株一起育种，我们产生了双突变体，其具有在单个突变纯合小鼠中不明显的显著表型。前肢的桡骨和尺骨几乎完全消失，中轴骨骼显示同源异型转化，并且有严重的肾脏缺陷，这在任何一个突变体中都不存在。肢体和中轴表型是定量的：随着更多的突变等位基因被添加到基因型中，表型变得越来越严重。这种非典型的骨骼缺陷表明，旁系同源的Hox基因共同发挥作用，以指定肢体的生长和图案沿着proximodistal轴。
MICE with targeted disruptions(1) in Hox genes have been generated to evaluate the role of the Hox complex in determining the mammalian body plan. This complex of 38 genes encodes transcription factors that specify regional information along the embryonic axes. Early in vertebrate evolution an ancestral complex shared with invertebrates was duplicated twice to give rise to the four linkage groups (Hox A, B, C and D)(2,3). As a consequence, corresponding genes on the separate linkage groups, called paralogues, are most closely related to each other. Based on sequence similarities, the Hox genes have been subdivided into 13 paralogous groups. The five most 5' groups (Hox 9-13) pattern the posterior region of the vertebrate embryo and the appendicular skeleton(4-18). Mice with individual mutations in the paralogous genes hoxa-11 and hoxd-11 have been described(15-18). By breeding these two strains together we have generated double mutants which have dramatic phenotypes not apparent in mice homozygous for the individual mutations. The radius and the ulna of the forelimb are almost entirely eliminated, the axial skeleton shows homeotic transformations, and there are severe kidney defects not present in either single mutant. The limb and axial phenotypes are quantitative: as more mutant alleles are added to the genotype, the phenotype becomes progressively more severe. The appendicular skeleton defects suggest that paralogous Hox genes function together to specify limb outgrowth and patterning along the proximodistal axis.