Roles of transcription factors in kidney development

转录因子在肾脏发育中的作用

• 批准号: 8102978
• 负责人: PIN-XIAN XU
• 金额: $ 36.13万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102978
• 关键词: Address; Affect; Applications Grants; Branchio-Oto-Renal Syndrome; Cell Lineage; Complex; Congenital Abnormality; Consensus; Cultured Cells; DNA Binding; Data; Defect; Development; Disease; GDNF gene; Gene Proteins; Gene Targeting; Genes; Grant; Growth and Development function; Health; Human; In Vitro; Kidney; Lead; Link; MAP Kinase Modules; Mammals; Mediating; Mesenchyme; Metanephric Diverticulum; Mitogen-Activated Protein Kinases; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Organ; Pathogenesis; Patients; Pattern; Pattern Formation; Phenotype; Phosphorylation; Play; Prevention; Process; Proteins; Regulation; Role; Severities; Signal Transduction; Site; Specific qualifier value; Stem cells; System; Testing; To specify; Ureter; Urologic Diseases; base; in vivo; insight; mouse model; mutant; nephrogenesis; promoter; protein expression; repaired; research study; transcription factor; urinary tract obstruction

DESCRIPTION (provided by applicant): In mammals, kidney development involves the specification of the metanephric mesenchyme (MM), the outgrowth of the ureteric bud (UB), and it's correctly patterned branching morphogenesis to generate the ureter and the renal collecting system. It is known that GDNF/Ret signaling plays a central role in these processes in mice. However, the genes that control the specification of MM and pattern the UB and its branching morphogenesis, and the regulatory mechanism of Gdnf expression in the MM are still poorly understood. The long-term objective of this proposal is to elucidate the mechanisms by which Eya1 and Six1 control normal kidney development. Defects in these genes in humans cause Branchio-Oto-Renal (BOR) syndrome, a congenital birth defect characterized by combinations of branchial, otic and renal anomalies. To understand the developmental and molecular bases of renal defects that occur in BOR syndrome, we analyzed the mutations identified in the EYA1 and SIX1 genes from BOR patients functionally and generated Eya1 and Six1 mutant mice through gene targeting. Our results indicate that Eya1 specifies the MM and is a critical regulator for Gdnf expression in the MM. We found that Eya1 acts upstream of Six1 but both gene products interact during kidney development. Furthermore, we have shown that Six1 is a critical regulator for branching morphogenesis by mediating the expression of Gdnf, Six2 and Pax2 in the MM. We also demonstrated that the mutations identified in either the EYA1 or SIX1 gene from BOR patients affected either Eya1-Six1 interaction or Six1-DNA binding, thus providing new insights into the molecular basis of renal developmental diseases in humans. This application will continue to define the molecular and developmental mechanisms by which the Eya1 and Six1 drive normal kidney development. First, we will investigate the mechanisms by which Eya1 specifies the MM and drives normal nephrogenesis. Next, we will investigate the regulation of Eya1 activity in kidney development. Lastly, we will define the mechanism by which Six1 initiates branching morphogenesis. These studies should lead to significant improvements in our understanding of the multilayer control mechanisms by Eya1-Six1 that mediate development of a normal kidney. In addition, these results will provide important insights into the developmental and molecular pathogenesis of renal defects occurring in BOR syndrome. PUBLIC HEALTH RELEVANCE: Narratives: Congenital kidney and urinary tract disorders, including renal agenesis and hypodysplasia and urinary tract obstruction, are the most common types of birth defects. This grant application proposes to elucidate the molecular and developmental pathogenesis of these congenital diseases and address several key questions of when and how a set of transcription factors act to mediate development of a normal ureter and kidney. Identifying the genes and proteins and understanding their roles and functions in the development and growth of the kidney from a small group of progenitor cells to a complex organ may eventually lead to prevention or repair of such birth defects.

描述（由申请人提供）：在哺乳动物中，肾脏发育涉及后肾间充质（MM）的规范、输尿管芽（UB）的生长，以及生成输尿管和肾集合系统的正确模式的分支形态发生。众所周知，GDNF/Ret 信号传导在小鼠的这些过程中发挥着核心作用。然而，控制 MM 规格、形成 UB 及其分支形态发生的基因，以及 MM 中 Gdnf 表达的调控机制仍然知之甚少。该提案的长期目标是阐明 Eya1 和 Six1 控制正常肾脏发育的机制。人类这些基因的缺陷会导致鳃-耳-肾（BOR）综合征，这是一种先天性出生缺陷，其特征是鳃、耳和肾异常的组合。为了了解 BOR 综合征中发生的肾脏缺陷的发育和分子基础，我们对 BOR 患者的 EYA1 和 SIX1 基因中发现的突变进行了功能性分析，并通过基因打靶产生了 Eya1 和 Six1 突变小鼠。我们的结果表明 Eya1 指定 MM，并且是 MM 中 Gdnf 表达的关键调节因子。我们发现 Eya1 在 Six1 的上游发挥作用，但两种基因产物在肾脏发育过程中相互作用。此外，我们还发现 Six1 通过介导 MM 中 Gdnf、Six2 和 Pax2 的表达，是分支形态发生的关键调节因子。我们还证明，在 BOR 患者的 EYA1 或 SIX1 基因中发现的突变影响 Eya1-Six1 相互作用或 Six1-DNA 结合，从而为人类肾脏发育疾病的分子基础提供了新的见解。该申请将继续定义 Eya1 和 Six1 驱动正常肾脏发育的分子和发育机制。首先，我们将研究 Eya1 指定 MM 并驱动正常肾发生的机制。接下来，我们将研究Eya1活性在肾脏发育中的调节。最后，我们将定义 Six1 启动分支形态发生的机制。这些研究应该会显着提高我们对 Eya1-Six1 介导正常肾脏发育的多层控制机制的理解。此外，这些结果将为 BOR 综合征中肾脏缺陷的发育和分子发病机制提供重要见解。公共卫生相关性：叙述：先天性肾脏和泌尿道疾病，包括肾发育不全、发育不良和尿路梗阻，是最常见的出生缺陷类型。该拨款申请旨在阐明这些先天性疾病的分子和发育发病机制，并解决一组转录因子何时以及如何作用以介导正常输尿管和肾脏发育的几个关键问题。识别基因和蛋白质并了解它们在肾脏从一小群祖细胞到复杂器官的发育和生长过程中的作用和功能可能最终有助于预防或修复此类出生缺陷。