DIX5 HOMEOBOX GENE CONTROL OF CRANIOFACIAL MORPHOGENESIS

DIX5 同源盒基因控制颅面形态发生

• 批准号: 6651294
• 负责人: THOMAS LUFKIN
• 金额: $ 12.62万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651294
• 关键词: congenital oral /facial /cranial defect; developmental genetics; gene targeting; genetically modified animals; homeobox genes; laboratory mouse; mammalian embryology

Fetal development of the mammalian craniofacial region is a complex embryological process which is poorly understood at the molecular level. Early in embryonic life the mammalian craniofacial region is first manifested as a blastema-like structure of paired branchial arches comprised primary of neural crest-derived mesenchymal cells. These neural crest cells acquires some of their patterning information prior to emigration from the hindbrain, and additional patterning information is imparted to them during their migration into the branchial arches. Several homeobox-containing DNA-binding transcriptional regulations have been identified which direct certain aspects of the morphogenesis and cellular differentiation of the craniofacial region. Here we describe a Dlx5 a new homeobox-containing gene of the distal less (Dlx) family which is most strongly expressed in the mesenchyme of the developing craniofacial region. Based upon its embryonic expression pattern, and the mode of action of other Dlx homeobox-contain genes, Dlx5 has the potential of being a major director normal morphogenesis and cellular differentiation of branchial arch derived structures. To understand the genetic basis of embryonic development of the craniofacial region, we propose to alter the normal function of the homeobox Dlx5 which shows highly restricted expression in the branchial arches (as well as the perichondrial region of all skeletal elements). In addition, we will identify and characterize the DNA cis-regulatory elements which direct regionally-restricted Dlx5 gene expression in the developing craniofacial region. To this end, we will rely primarily on the transgenic mouse technology that we have developed and refined over the last eight years. Accordingly, (I) we will generate a disruption (gene knock-out) of Dlx5. (II) We will determine the DNA regulatory elements which control Dlx5 craniofacial-specific gene expression. Results of these experiments will help clarify the role of Dlx5 in normal craniofacial morphogenesis. This is in keeping with our long range goal which is to understand the molecular mechanisms involved in directing mammalian craniofacial development with the belief that such knowledge will eventually be used to correct either trauma to, or genetic defects of the craniofacial region.

哺乳动物颅面区域的胚胎发育是一个复杂的胚胎学过程，在分子水平上了解甚少。哺乳动物颅面区在胚胎早期首先表现为由神经嵴来源的间充质细胞组成的成对鳃弓的芽细胞样结构。这些神经嵴细胞在从后脑迁移之前获得一些图案信息，并且在迁移到鳃弓期间向它们传递额外的图案信息。已经确定了几个含有同源框的DNA结合转录调控，其指导颅面区域的形态发生和细胞分化的某些方面。在这里，我们描述了一个新的同源框含有基因的远端少（DLX）家庭，这是最强烈的表达在间充质的发展颅面区域。基于其胚胎表达模式和其他Dlx同源框基因的作用模式，Dlx 5具有成为鳃弓衍生结构的正常形态发生和细胞分化的主要指导者的潜力。为了了解颅面区域胚胎发育的遗传基础，我们建议改变同源框Dlx 5的正常功能，该同源框Dlx 5在鳃弓（以及所有骨骼元素的软骨膜区域）中显示出高度限制的表达。此外，我们将确定和表征的DNA顺式调控元件，直接区域限制Dlx5基因表达的发展颅面区域。为此，我们将主要依靠我们在过去八年中开发和完善的转基因小鼠技术。因此，（I）我们将产生Dlx 5的破坏（基因敲除）。(II)我们将确定控制Dlx5颅面特异性基因表达的DNA调控元件。这些实验的结果将有助于阐明Dlx 5在正常颅面形态发生中的作用。这与我们的长期目标是一致的，即了解参与指导哺乳动物颅面发育的分子机制，相信这些知识最终将用于纠正颅面区域的创伤或遗传缺陷。