Hex-a Homeobox Gene Essential for Liver Development

Hex-a 同源盒基因对肝脏发育至关重要

• 批准号: 6525201
• 负责人: CLIFFORD W BOGUE
• 金额: $ 40.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6525201
• 关键词: bile ducts; developmental genetics; embryogenesis; endoderm; gastrointestinal system; gene induction /repression; gene mutation; gene targeting; genetically modified animals; histogenesis; homeobox genes; laboratory mouse; liver; liver cells; mammalian embryology; mesoderm; nucleic acid sequence

DESCRIPTION (Provided by Applicant): To study the roles that homeobox genes play in organogenesis, mice with a null mutation of the divergent homeobox gene Hex were generated. These mice prove that Hex is essential for liver specification and budding. Hex is the first gene known to be necessary for this critical developmental event - an event that is dependent upon inductive signaling between the foregut endoderm and adjacent cardiac mesoderm. Hex expression, in addition to being restricted to the ventral foregut endoderm at the stage of liver specification and budding (E8.5), is also seen in the liver throughout all stages of embryogenesis and in the mature liver, in mature hepatocytes as well as the bile duct epithelium of intra- and extra-hepatic bile ducts and the gall bladder. In this proposal the following hypotheses will be tested: I) Hex controls the inductive events in embryonic foregut endoderm and adjacent cardiac mesoderm necessary for liver bud formation and determination of the hepatic cell phenotype; 2) Hex is necessary for the differentiation of hepatoblasts into hepatocytes and biliary epithelial cells and for bile duct formation: and 3) there are specific enhancer elements that direct Hex expression in the foregut and liver. To test these hypotheses and to provide insight into tile role Hex plays in the development and function of the liver, three specific aims are proposed. 1. To define the function of Hex in hepatic specification and liver bud formation by analyzing the expression of liver-enriched transcription factors and signaling molecules in Hex -/- mice and by performing tissue recombination between wild-type and mutant hepatic endoderm and cardiac mesoderm in culture. 2. To determine the role of Hex in the differentiation of hepatoblasts into mature hepatocytes and bile duct cells and in bile duct formation using Hex conditional knockout mice. 3. To determine the enhancer elements directing Hex expression in the foregut endoderm and liver in vivo in order to identify the transcription factors regulating liver-specific expression of Hex. The long-term goal of this project to discover novel pathways directing liver development and liver cell differentiation in vivo using the powerful tools of mouse genetics. The knowledge gained from these studies is applicable to the diagnosis and treatment of many debilitating childhood liver disorders, including biliary atresia, bile duct paucity syndromes, and repair from injury. In addition, the insight gained by our studies of the determination of hepatic cell types will contribute greatly to the effort to derive functional hepatocytes from multi-potential stem cells.

描述（申请人提供）： 为了研究同源异型盒基因在器官形成中的作用， 产生趋异同源盒基因Hex的突变。这些老鼠证明了 Hex对肝脏的特化和萌芽至关重要。Hex是第一个 一个已知的基因是必要的这一关键的发展事件-一个事件 这取决于前肠内胚层和 邻近心脏中胚层。十六进制表达式，除了被限制为 腹前肠内胚层在肝脏特化和出芽阶段 （E8.5），也见于整个胚胎发生的所有阶段的肝脏和 成熟的肝脏，在成熟的肝细胞以及胆管上皮细胞中， 肝内和肝外胆管以及胆囊。在这项提案中， 将测试以下假设：I）Hex控制感应事件， 胚胎前肠内胚层和邻近的心脏中胚层是肝脏必需的 芽形成和肝细胞表型的确定; 2）Hex是 成肝细胞分化为肝细胞和胆管细胞所必需的 上皮细胞和胆管形成：和3）有特定的 在前肠和肝脏中指导Hex表达的增强子元件。测试 这些假设，并提供深入了解瓷砖的作用六角发挥在 为了研究肝脏的发育和功能，提出了三个具体目标。1.到 定义Hex在肝特化和肝芽形成中的功能， 分析肝脏富集的转录因子和信号传导的表达 Hex-/-小鼠中的分子，并通过在 培养的野生型和突变型肝内胚层和心脏中胚层。2.到 确定Hex在成肝细胞分化为成熟细胞中的作用 肝细胞和胆管细胞以及使用Hex的胆管形成 条件性基因敲除小鼠3.为了确定指导Hex的增强子元件， 在体内前肠内胚层和肝脏中的表达，以鉴定 调节Hex肝脏特异性表达的转录因子。的 该项目的长期目标是发现新的途径， 体内发育和肝细胞分化的强大工具， 小鼠遗传学从这些研究中获得的知识适用于 诊断和治疗许多使人衰弱的儿童肝脏疾病， 包括胆道闭锁、胆管缺乏综合征和损伤修复。 此外，通过我们对肝细胞的测定的研究， 细胞类型将大大有助于获得功能性的 多潜能干细胞的肝细胞。