Genetic analysis of Pea3 transcription factors and kidney development

Pea3转录因子与肾脏发育的遗传分析

基本信息

批准号：
7913607
负责人：
FRANKLIN D COSTANTINI
金额：
$ 9.73万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7913607
关键词：
A Mouse Address Affect Alleles Animals Behavior Cell Lineage Cells Clinical Computer Systems Development Congenital Abnormality Data Defect Development ETV1 gene Epithelial Event FGF10 gene FGF7 gene FGFR2 gene Failure Family Fibroblast Growth Factor GDNF gene Gene Expression Gene Targeting Genes Genetic Genitourinary system Goals Growth Growth Factor Human Hypertension Individual Kidney Kidney Diseases Knock-out Knockout Mice Lead Mediating Mesenchyme Metanephric Diverticulum Modeling Morphogenesis Mus Mutant Strains Mice Mutation Nephrons Organ Organ Culture Techniques Organogenesis Pathway interactions Pattern Phenotype Play Process Publishing Receptor Protein-Tyrosine Kinases Research Personnel Role Signal Pathway Signal Transduction Structure System Testing Tissues Transgenic Organisms Ureter base body system cell type embryonic stem cell factor C gain of function genetic analysis in vivo loss of function member mutant nephrogenesis programs response transcription factor

项目摘要

DESCRIPTION (provided by applicant): While GDNF signaling through the Ret receptor tyrosine kinase is essential for renal development in mice and in humans, the events that occur downstream of Ret to promote ureteric bud (UB) branching morpho- genesis remain largely obscure. This proposal concerns two closely related transcription factors, Pea3 and Erm, which are known targets of FGF signaling in other organs. Our preliminary data indicate that Pea3 and Erm are required for normal ureter and kidney development, and that they function downstream of GDNF/ Ret signaling in this process. However, it is unclear if their role is restricted to the ureteric bud, or whether they also function in the metanephric mesenchyme lineage. Our overall goal is to elucidate the role of these transcription factors in development of the excretory system, and to determine why mutations in Pea3 and Erm lead to renal agenesis and hypodysplasia. We will use a variety of in vivo genetic approaches, together with an organ culture system, to address several questions: In what cell lineage(s) in the developing kidney are these genes required? How is the behavior of individual mutant cells in genetically mosaic kidneys affected by their absence? Is the expression of Pea3 and Erm in the kidney regulated by FGFs as well as by GDNF? What downstream genes do these transcription factors regulate, which might explain their importance for branching morphogenesis? These studies will test a model in which GDNF and FGFs control the expression of Pea3 and Erm, which in turn regulate a "battery" of effector genes that mediate the effects of these growth factors on branching morphogenesis. Understanding the mechanisms by which Pea3 and Erm promote UB growth and branching, when activated by specific growth factors, is not only an important basic problem in the genetic control of organogenesis. It also has important clinical implications, as renal agenesis, hypodysplasia and ureteral defects are common birth defects, which can often be attributed to abnormalities in the development of the UB. The pattern of branching morphogenesis of this epithelial tissue not only determines the structure of the collecting system - it also influences the number of nephrons, which is quite variable in humans, and is thought to influence the rate of progression of renal diseases and the development of hypertension. It is therefore possible that mutations in Pea3 and Erm may contribute to renal developmental defects in humans.

描述（由申请人提供）：虽然通过 Ret 受体酪氨酸激酶的 GDNF 信号传导对于小鼠和人类的肾脏发育至关重要，但 Ret 下游发生的促进输尿管芽（UB）分支形态发生的事件仍然很大程度上不清楚。该提案涉及两个密切相关的转录因子 Pea3 和 Erm，它们是其他器官中 FGF 信号传导的已知靶标。我们的初步数据表明 Pea3 和 Erm 是正常输尿管和肾脏发育所必需的，并且它们在此过程中发挥 GDNF/Ret 信号下游的作用。然而，尚不清楚它们的作用是否仅限于输尿管芽，或者它们是否也在后肾间充质谱系中发挥作用。我们的总体目标是阐明这些转录因子在排泄系统发育中的作用，并确定为什么 Pea3 和 Erm 突变会导致肾发育不全和发育不良。我们将使用各种体内遗传方法以及器官培养系统来解决几个问题：发育中的肾脏中的哪些细胞谱系需要这些基因？基因嵌合肾中单个突变细胞的行为如何因它们的缺失而受到影响？肾脏中 Pea3 和 Erm 的表达是否受 FGF 和 GDNF 调节？这些转录因子调节哪些下游基因，这可能解释它们对分支形态发生的重要性？这些研究将测试一个模型，其中 GDNF 和 FGF 控制 Pea3 和 Erm 的表达，而 Pea3 和 Erm 反过来又调节效应基因的“电池”，介导这些生长因子对分枝形态发生的影响。了解 Pea3 和 Erm 在被特定生长因子激活时促进 UB 生长和分支的机制不仅是器官发生遗传控制中的一个重要基本问题。它还具有重要的临床意义，因为肾发育不全、发育不良和输尿管缺陷是常见的出生缺陷，通常可归因于 UB 发育异常。这种上皮组织的分支形态发生模式不仅决定了集合系统的结构，还影响肾单位的数量，而肾单位的数量在人类中差异很大，并且被认为会影响肾脏疾病的进展速度和肾病的发展。高血压。因此，Pea3 和 Erm 的突变可能导致人类肾脏发育缺陷。