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(改编自调查人员的摘要)：基于他们的 胚胎表达结构域及其主要研究结果 研究人员的基因敲除研究如下，Dlx5和Dlx6 同源框基因是形态发生和细胞发育的主要指导者 胎儿骨骼的分化。Dlx5和Dlx6也属于 人类裂手/裂足发育的候选临界区 失调症(OMIM1996)，也称为指(趾)症(Caldwell，183600；Crackower et 等人，1996年)。如下所示，首席调查员已经做出了 同时击倒Dlx5和Dlx6(Dlx5/6)。这两个基因都位于 在染色体上相隔几个kb，两个基因的定向缺失是 同时删除，因为组合的Dlx5和Dlx6空鼠标不能 通过单个Dlx5和Dlx6基因敲除的简单交配实现，如 这两个基因联系得太紧密了。严密观察的肢体缺陷 人类裂手/裂足遗传性表型概述 畸形。IRPG项目3的Bruce Gelb博士正在追求人类的方面 这项工作。其余的Dlx5/6缺失表型表现为严重的 颅面、枢椎和附件的骨骼。目前还不清楚的是， 并是本次提案(IRPG项目4)的主要着力点如下： Dlx5和Dlx65的个体贡献是什么 表型影响胎儿骨骼的每个主要部分；2)什么是 发展的行为方式就是这两个基因；3)它们的位置是什么 在骨骼模式基因的层次中；以及4)它们的机制是什么 具有时空胚胎转录调控作用。