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胎儿发育是一个复杂的胚胎学过程，在分子水平上尚不清楚。在胚胎生命的早期，哺乳动物颅面区域首先被表现为成对的分支拱形的胚芽样结构，该结构由神经rest衍生的间充质细胞组成。这些神经rest细胞在从后脑移民之前获取了一些图案信息，并且在将其迁移到分支拱门时，将授予它们的其他图案信息。已经确定了几种含同基因的DNA结合转录法规，这些调节指导了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DLX5远端（DLX）家族的新型含同源物氧的基因，该基因在发育中的颅面区域的间隙中最强烈表达。 DLX5基于其胚胎表达模式以及其他DLX同源核心符号基因的作用方式，具有成为主要导演的正常形态发生和分支拱形衍生结构的细胞分化。为了了解颅面区域的胚胎发育的遗传基础，我们建议改变同型ox dlx5的正常功能，该功能显示出在分支拱门中显示高度限制的表达（以及所有骨骼元素的per骨区域）。此外，我们将识别并表征DNA顺式调节元件，这些元素将在发育中的颅面区域中引导区域限制的DLX5基因表达。为此，我们将主要依靠过去八年来开发和完善的转基因小鼠技术。因此，（i）我们将产生DLX5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调节元件。这些实验的结果将有助于阐明DLX5在正常颅面形态发生中的作用。这与我们的远距离目标保持一致，即了解指导哺乳动物颅面发育中涉及的分子机制，认为最终将使用此类知识来纠正颅面区域的创伤或遗传缺陷。