GENETIC CONTROL OF LIMB DEVELOPMENT

该计划的目的是研究分子调控， 在发育中的脊椎动物肢体中形成图案，并开始 应用这些基本知识来理解人类遗传的本质， 影响肢体模式的疾病在项目1中， 细胞凋亡在维持顶端外胚层的活性中起作用 脊（AER），指导肢体生长和模式将是 研究，将相关的假设，同源异型盒- 含有Msx-2基因和BMP的基因在一个调控网络中， AER中的程序性细胞死亡。假设同源异型盒- 含有基因Cux-，果蝇Cut基因的脊椎动物同源物， AER。假设含有同源框的Cux，脊椎动物 果蝇Cut基因的同源物，在调节 分割过程的开始，该分割过程生成 此外，亦会研究肢体的骨骼元素。在项目2中， 含同源框基因Dlx-5之间的作用和关系， 生长因子IGF-1、TGF-α和FGF-10在建立 外侧板的假定肢体区域，以及初始的 将研究从这些区域形成分支。在 项目3，调控表达的转录机制 将研究Msx-2在发育中的脊椎动物肢体中的表达。特别 重点将是鉴定顺式调节元件， 反式作用因子控制独立调节的空间- Msx-2表达的特定结构域和 控制Msx-2的独立调节的空间特异性结构域 在AER和中胚层中表达。在项目4中， 分析和定位克隆策略将用于定位基因座 找出导致人类遗传缺陷的基因 手裂-足裂-4种畸形和手足畸形， 由发育障碍引起的遗传性疾病 四肢的图案。核心单位将为项目提供 无趾和多趾突变鸡胚将用于 分析调控基因和信号分子在 模式化该计划的综合目标是研究自然， 一些基因的调节、相互作用和作用机制 以及参与形成、生长和 脊椎动物肢体的模式，并开始应用这个基本的 人类遗传性疾病的性质影响肢体 模式化

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 role that apoptosis plays in maintenance of the activity of the apical ectodermal ridge (AER) that directs limb outgrowth and patterning will be investigated, as will the related hypothesis that the homeobox- containing gene Msx-2 and BMPs are in a regulatory network that controls programmed cell death in the AER. The hypothesis that the homeobox- containing gene Cux-, the vertebrate homolog of the Drosophila Cut gene, AER. The hypothesis that the homeobox-containing Cux, the vertebrate homolog of the Drosophila Cut gene, plays a critical role in regulation the onset of the segmentation process that generates joints between the skeletal elements of the limb will also be studied. In Project 2, the roles and relationships among the homeobox-containing gene Dlx-5, and the growth factors IGF-1, TGF-alpha, and FGF-10 in the establishment of the presumptive limb regions of the lateral plate, and the initial formation of the limb from these regions will be investigated. In Project 3, the transcriptional mechanisms that regulate the expression of Msx-2 in the developing vertebrate limb will be studied. Particular emphasis will be on identification of the cis-regulatory elements and trans-acting factors that control the independently-regulated spatially- specific domains of Msx-2 expression and transacting factors that control the independently-regulated spatially-specific domains of Msx-2 expression in the AER and mesoderm. In Project 4, genetic linkage analyses and positioning cloning strategies will be used to map the loci of and identify the genes responsible for the human genetic defects Split Hand-Split Foot-4 malformations and Acheiropodia, which are genetic disorders that result from impairments in developmental patterning of the limbs. A Core unit will supply the Projects with amelic and polydactylous mutant chick embryos that will be used in the analysis of the roles of regulatory genes and signaling molecules in patterning. The integrated goal of the Program is to study the nature, regulation, interactions, and mechanisms of action of some of the genes and signaling molecules involved in the formation, outgrowth, and patterning of the vertebrate limb, and to begin to apply this basic knowledge the nature of human genetic disorders affecting limb patterning.