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: 6654868
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654868
• 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(由申请人提供)： 为了研究同源框基因在器官发生中所起的作用，携带空基因的小鼠 产生了发散的同源异型盒基因Hex的突变。这些老鼠证明了 十六进制对于肝脏的规格和萌发是必不可少的。希克斯是第一个 已知对这一关键发育事件--事件--所必需的基因 这取决于前肠内胚层和前肠内胚层之间的诱导信号。 邻近的心脏中胚层。十六进制表达式，除了被限制为 肝脏特异期和发芽期的前肠腹侧内胚层 (E8.5)，也在肝脏中发现，在胚胎发育的所有阶段和在 成熟的肝脏，成熟的肝细胞以及胆管上皮 肝内外胆管和胆总管。在这份提案中， 将检验以下假设：i)十六进制控制 肝脏必需的胚胎前肠内胚层和邻近的心脏中胚层 芽形成和肝细胞表型的测定；2)十六烷基硫酸酯 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：以及3)有特异性的 在前肠和肝脏中指导十六进制表达的增强子元件。为了测试 这些假设，并提供对十六进制在 关于肝脏的发育和功能，提出了三个具体目标。1.至 通过以下方式确定Hex在肝脏规格和肝芽形成中的作用 分析肝脏富集型转录因子的表达及其信号转导 Hex-/-小鼠体内的分子，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.至 确定Hex在肝母细胞向成熟分化中的作用 肝细胞和胆管细胞及其在胆管形成中的应用 条件基因敲除小鼠。3.确定引导十六进制的增强子元件 在体内前肠内胚层和肝脏中的表达 调节肝脏特异性Hex表达的转录因子。这个 该项目的长期目标是发现引导肝脏的新途径 利用强大的工具进行体内发育和肝细胞分化 老鼠遗传学。从这些研究中获得的知识适用于 许多衰弱的儿童肝病的诊断和治疗， 包括胆道闭锁、胆管稀少综合征、损伤修复等。 此外，我们通过对肝脏的测定的研究所获得的见解 细胞类型将对衍生功能的努力做出巨大贡献 多潜能干细胞来源的肝细胞。