Genetic analysis of Pea3 transcription factors and kidney development

描述（由申请人提供）：虽然通过Ret受体酪氨酸激酶的GDNF信号传导对小鼠和人类肾脏发育至关重要，但Ret下游发生的促进输尿管芽（UB）分支形态发生的事件在很大程度上仍然不清楚。这一建议涉及两个密切相关的转录因子Pea3和Erm，它们是其他器官中已知的FGF信号传导的靶点。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，并且在这一过程中它们在GDNF/ Ret信号传导的下游发挥作用。然而，目前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质谱系中起作用。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Pea3和Erm突变导致肾脏发育不全和发育不良的原因。我们将使用多种体内遗传方法，连同器官培养系统，来解决以下几个问题：在发育中的肾脏的哪些细胞系中需要这些基因？基因镶嵌肾中单个突变细胞的行为如何受到其缺失的影响？Pea3和Erm在肾脏中的表达是否受到FGFs和GDNF的调节？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GDNF和FGFs控制Pea3和Erm表达的模型，Pea3和Erm反过来调节调节这些生长因子对分支形态发生影响的效应基因的“电池”。了解Pea3和Erm在特定生长因子激活下促进UB生长和分支的机制，不仅是器官发生遗传控制的重要基础问题。它也具有重要的临床意义，因为肾脏发育不全、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收集系统的结构，还影响了肾单位的数量，这在人类中是非常可变的，并且被认为影响肾脏疾病的进展速度和高血压的发展。因此，Pea3和Erm的突变可能导致人类肾脏发育缺陷。

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.