DLX HOMEOBOX GENE CONTROL OF FETAL SKELETOGENESIS

胎儿骨骼形成的 DLX 同源框基因控制

• 批准号: 6516614
• 负责人: THOMAS LUFKIN
• 金额: $ 32.71万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516614
• 关键词: bone development; cell differentiation; developmental genetics; embryo /fetus tissue /cell culture; embryogenesis; gene expression; gene mutation; genetic enhancer element; genetic models; genetic promoter element; genetic regulation; genetic transcription; genetically modified animals; histogenesis; homeobox genes; laboratory mouse; phenotype; skeletal system

DESCRIPTION (adapted from the Investigator's abstract): Based upon their embryonic expression domains and the preliminary results from the Principal Investigator's gene knockout studies presented below, the Dlx5 and Dlx6 homeobox genes are major directors of morphogenesis and cellular differentiation of the fetal skeleton. Dlx5 and Dlx6 also fall within the candidate critical region for the human split hand/split foot developmental disorder (OMIM 183600), also termed ectrodactyly (Caldwell, 1996; Crackower et al., 1996). As demonstrated below, the Principal Investigator has already made a simultaneous knockout of both Dlx5 and Dlx6 (Dlx5/6). Both genes are located a few kb apart on the chromosome, and a targeted deletion of both genes was deleted simultaneously, since the combined Dlx5 and Dlx6 null mouse cannot be achieved by simple intermating of the individual Dlx5 and Dlx6 knockouts, as the two genes are too closely linked. The limb defects observed closely recapitulate the phenotype of the human split hand/split foot inherited human malformation. Dr. Bruce Gelb, IRPG project 3, is pursuing the human aspect of this work. The remaining Dlx5/6 null phenotype shows a severe dysmorphology of craniofacial, axial and appendicular skeleton. What is unclear at this point, and is the primary focus of this proposal (IRPG project 4) is the following: 1) what the individual contribution of Dlx5 and Dlx65 is to this striking phenotype affecting each major subdivision of the fetal skeleton; 2) what the developmental mode of action is of these two genes; 3) what their position is within the hierarchy of skeletal patterning genes; and 4) what their mechanism is of spatiotemporal embryonic transcriptional regulation.

描述（改编自研究者的摘要）：基于他们的 胚胎表达域和校长的初步结果 下面介绍研究者的基因敲除研究，Dlx5 和 Dlx6 同源框基因是形态发生和细胞的主要指导者 胎儿骨骼的分化。 Dlx5 和 Dlx6 也属于 人类裂手/裂脚发育的候选关键区域 疾病（OMIM 183600），也称为外指症（Caldwell，1996；Crackower 等 等，1996）。如下所示，首席研究员已经做出了 同时敲除 Dlx5 和 Dlx6 (Dlx5/6)。两个基因都位于 染色体上相距几kb，两个基因的定向删除是 同时删除，因为组合的 Dlx5 和 Dlx6 空鼠标不能 通过简单地组合单个 Dlx5 和 Dlx6 敲除来实现，如 这两个基因联系太紧密了。密切观察肢体缺陷 概括了人类分手/分脚遗传性人类的表型 畸形。 IRPG 项目 3 的 Bruce Gelb 博士正在追求人性化的一面 这项工作。剩余的 Dlx5/6 无效表型显示出严重的畸形 颅面、中轴和四肢骨骼。目前尚不清楚的是， 本提案（IRRPG 项目 4）的主要重点如下：1) Dlx5 和 Dlx65 对这一惊人的成果有何贡献？ 影响胎儿骨骼每个主要细分的表型； 2）什么 发育作用模式是这两个基因的作用； 3）他们的立场是什么 在骨骼图案基因的层次结构内； 4）它们的机制是什么 具有胚胎时空转录调控作用。