GENETIC CONTROL OF LIMB DEVELOPMENT

该计划的目的是研究细胞的分子调控。 在脊椎动物肢体发育中的图案形成，并开始应用 这些基本知识有助于理解人类遗传性疾病的本质 影响肢体图案。在项目1中，角色和关系 同源异型盒基因MSX2和D1X-5之间的相互作用 顶端外胚层脊(AER)的活动，起着至关重要的作用 在指导自由党的发展和模式方面，将进行研究， 它们在指认肢芽前中胚层中的作用。这个 D1x-5在调控肢体软骨分化起始和分化中的作用 软骨特异性基因的表达也将被调查。在项目中 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 我们将研究肢体的生长，以及这些生长的作用。 红豆杉体格发育初期形成肢芽的因素 雏鸡胚胎的侧板。在项目3中，深入分析 调控组织特异性表达的转录机制 MSX2在发育肢体的AER和前中胚层中的表达 在转基因小鼠中使用报告结构提供洞察力 MSX2基因是如何调节的，以及调节网络是如何调节的 参与图案形成的。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 指畸形，这是人类遗传性疾病的临床表现 症状提示四肢的发育模式有误。一个 核心单位将为项目1-3提供无釉和多指突变体 这将用于分析鸡胚的调控作用 图案化中的基因。该计划的综合目标是调查 一些病毒的性质、调节、相互作用和作用机制 参与雏鸟模式形成的基因和信号分子 肢体，并利用这一知识来理解人类遗传性疾病 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.