Vogt T F, Leder P
Department of Molecular Biology, Princeton University, New Jersey.
Dev Genet. 1996;19(1):33-42. doi: 10.1002/(SICI)1520-6408(1996)19:1<33::AID-DVG4>3.0.CO;2-1.
The study of limb development has provided insight into pattern formation during vertebrate embryogenesis. Genetic approaches offer powerful ways to identify the critical molecules and their pathways of action required to execute a complex morphogenetic program. We have applied genetic analysis to the process of limb development by studying two mouse mutants, limb deformity (ld) and Strong's luxoid (lst). These mutations confer contrasting phenotypic alterations to the anteroposterior limb pattern. The six mutant ld alleles are fully recessive and result in oligosyndactyly of all four limbs. By contrast, the two mutant lst alleles result in a mirror-image polydactylous limb phenotype inherited in a semidominant fashion. Morphological and molecular analysis of embryonic limbs has shown that the ld and lst alleles affect the extent and distribution of two key signaling centers differentially: the apical ectodermal ridge and the zone of polarizing activity. Molecular characterization of the ld gene has defined a new family of evolutionarily conserved proteins termed the formins. The underlying molecular defect in the lst mutation has not been identified; however, both loci are tightly linked on mouse chromosome 2, suggesting the possibility that they may be allelic. In this study, we have used genetic analysis to examine the epistatic and allelic relationships of ld and lst. We observed that in + ld/lst + double heterozygotes, a single mutant ld allele is able to suppress the semi-dominant polydactylous lst limb phenotype. By segregating the lst and ld loci in a backcross, we observed that these loci recombine and are separated by a genetic distance of approximately 6 cM. Therefore, while our observations demonstrate a genetic interaction between ld and lst, it is probable that ld and lst are not allelic. Instead, lst and ld may be operating either in a linear or in a parallel (bypass) genetic pathway to affect the limb signaling centers.
肢体发育的研究为脊椎动物胚胎发生过程中的模式形成提供了见解。遗传学方法为识别执行复杂形态发生程序所需的关键分子及其作用途径提供了有力手段。我们通过研究两个小鼠突变体——肢体畸形（ld）和斯特朗氏亮氨酸拉链（lst），将遗传分析应用于肢体发育过程。这些突变给肢体的前后模式带来了截然不同的表型改变。六个ld突变等位基因完全隐性，导致四肢均出现少指畸形。相比之下，两个lst突变等位基因导致镜像多指肢体表型，以半显性方式遗传。对胚胎肢体的形态学和分子分析表明，ld和lst等位基因以不同方式影响两个关键信号中心的范围和分布：顶外胚层嵴和极化活性区。ld基因的分子特征定义了一个新的进化保守蛋白家族，称为formin。lst突变潜在的分子缺陷尚未确定；然而，这两个基因座在小鼠2号染色体上紧密连锁，表明它们可能是等位基因。在本研究中，我们利用遗传分析来研究ld和lst的上位性和等位基因关系。我们观察到，在 + ld/lst + 双杂合子中，单个突变的ld等位基因能够抑制半显性多指lst肢体表型。通过在回交中分离lst和ld基因座，我们观察到这些基因座发生重组，并且被大约6厘摩的遗传距离隔开。因此，虽然我们的观察结果表明ld和lst之间存在遗传相互作用，但ld和lst很可能不是等位基因。相反，lst和ld可能以线性或平行（旁路）遗传途径发挥作用，以影响肢体信号中心。
