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: 6719058
• 负责人: THOMAS LUFKIN
• 金额: $ 22.15万
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719058
• 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（改编自研究者摘要）：基于其 胚胎表达结构域和主要的初步结果， 研究者的基因敲除研究如下，Dlx 5和Dlx 6 同源异型盒基因是形态发生和细胞分化的主要指导者。 胎儿骨骼的分化。Dlx 5和Dlx 6也落入本发明的范围内。 人类裂手/裂足发育的候选关键区域 疾病（OMIM 183600），也称为缺指（考德威尔，1996; Crackower et 例如，1996年）的报告。如下文所示，主要研究者已经 同时敲除Dlx 5和Dlx 6（Dlx 5/6）。这两个基因都位于 在染色体上相隔几kb，并有针对性地删除这两个基因， 同时删除，因为组合的Dlx 5和Dlx 6空鼠标不能 通过单独的Dlx 5和Dlx 6敲除的简单相互配合来实现， 这两个基因联系得太紧密了密切观察肢体缺损 概括了人类裂手/裂足遗传人类的表型 畸形布鲁斯盖尔布博士，IRPG项目3，正在追求人类方面的 这项工作剩余的Dlx 5/6无效表型显示出严重的畸形， 颅面、中轴和外骨骼。目前还不清楚的是， 本提案（IRPG项目4）的主要重点如下：1） Dlx 5和Dlx 65对这一惊人的 表型影响胎儿骨骼的每一个主要细分; 2） 这两个基因的发育作用方式; 3）它们的位置是什么 在骨骼模式基因的层次结构中;以及4）它们的机制是什么？ 具有时空胚胎转录调控的特点。

项目成果

Homeobox gene Sax2 deficiency causes an imbalance in energy homeostasis.

同源框基因 Sax2 缺陷会导致能量稳态失衡。

• DOI: 10.1002/dvdy.21320
• 发表时间: 2007
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Simon,Ruth;Lufkin,Thomas;Bergemann,AndrewD
• 通讯作者: Bergemann,AndrewD

Regulatory genomics: Insights from the zebrafish.

监管基因组学：来自斑马鱼的见解。

• 发表时间: 2012
• 期刊: Current topics in genetics
• 作者: Chatterjee,Sumantra;Lufkin,Thomas
• 通讯作者: Lufkin,Thomas