GENETIC CONTROL OF LIMB DEVELOPMENT

该计划的目的是研究分子调控， 模式形成在发展中的脊椎动物肢体，并开始应用 这些基本知识有助于理解人类遗传疾病的本质 影响肢体模式 在项目1中，角色和关系 同源框基因Msx 2和D1 x-5在调节 活性的顶端外胚层嵴（AER），这起着至关重要的作用 在指导生长和模式的图书馆，将被研究，因为将 它们在肢芽前中胚层特化中的作用。 的 D1 x-5在调节肢体软骨分化中的作用， 还将研究软骨特异性基因表达。 在项目 2、生长因子IGF-I和胰岛素在相互作用中的作用 AER和亚脊中胚层之间的相互作用， 将研究肢体的生长，以及这些生长的作用 在肢芽的最初形成的因素从体侧膜的 鸡胚的侧板。 在项目3中，深入分析 组织特异性表达的转录调控机制 msx 2在发育肢体的AER和前中胚层中的表达将是 在转基因小鼠中使用报告基因构建体进行， msx 2基因是如何调控的，调控网络是如何 参与模式的形成。 在项目4中，遗传连锁分析将 用于绘制人类软骨发育不良、Grebe综合征和 缺指，这是人类遗传性疾病，其中临床 表现表明四肢发育模式的错误。 一 核心单位将为项目1-3提供无趾和多趾突变体 鸡胚，将用于分析的作用，调节 基因在模式中。 该计划的总体目标是调查 一些因素的性质、调节、相互作用和作用机制 基因和信号分子参与了小鸡的模式化 肢体，并利用这些知识来了解人类遗传疾病的 四肢

The objective of the Program is to study the molecular regulation of pattern formation in the developing vertebrate limb, and to begin to apply this basic knowledge to understanding the nature of human genetic disorders affecting limb patterning. In Project 1, the roles and relationships between the homeobox-containing genes Msx2 and D1x-5 in the regulation of activity of the apical ectodermal ridge (AER), which plays a crucial role in directing outgrowth and patterning of the lib, will be studied, as will their roles in specification of the anterior mesoderm of the limb bud. The role of D1x-5 in regulating the onset of limb cartilage differentiation and cartilage-specific gene expression will also be investigated. In Project 2, the roles of the growth factors IGF-I and insulin in the reciprocal interactions between the AER and subridge mesoderm that are responsible for outgrowth of the limb will be studied, as will the roles of these growth factors in the initial formation of the limb bud from the somatopleure of the lateral plate of the chick embryo. In Project 3, an in-depth analysis of the transcriptional mechanisms regulating the tissue-specific expression of msx2 in the AER and anterior mesoderm of the developing limb will be undertaken using reporter constructs in transgenic mice to provide insight into how the msx2 gene is regulated and how the regulatory network is involved in pattern formation. In Project 4, genetic linkage analyses will be used to map the loci of the human chondrodysplasias, Grebe syndrome and ectrodactyly, which are human genetic disorders in which the clinical manifestations suggest errors in developmental patterning of the limbs. A Core unit will supply Projects 1-3 with amelic and polydactylous mutant chick embryos that will be used in the analysis of the roles of regulatory genes in patterning. The integrated goal of this Program is to investigate the nature, regulation, interactions, and mechanisms of action of some of the genes and signalling molecules involved in the patterning of the chick limb, and to use this knowledge to understand human genetic disorders of the limb.