Genetic analysis of Pea3 transcription factors and kidney development

描述（由申请人提供）：虽然GDNF通过Ret受体酪氨酸激酶的信号传导对于小鼠和人的肾发育是必需的，但是在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不清楚。该提议涉及两种密切相关的转录因子Pea 3和Erm，它们是其他器官中FGF信号传导的已知靶点。我们的初步数据表明，Pea 3和Erm是正常输尿管和肾脏发育所必需的，并且在此过程中它们在GDNF/ Ret信号传导的下游起作用。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充质谱系中起作用。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，并确定为什么Pea 3和Erm突变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，连同器官培养系统，以解决几个问题：在什么细胞谱系（S）在发展中的肾脏需要这些基因？在基因嵌合的肾脏中，个体突变细胞的行为如何受到它们缺失的影响？Pea 3和Erm在肾脏中的表达是否受FGF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枝形态发生的重要性？这些研究将测试一个模型，其中GDNF和FGF控制Pea 3和Erm的表达，这反过来又调节一个“电池”的效应基因，介导这些生长因子对分支形态发生的影响。了解Pea 3和Erm促进UB生长和分支的机制，当被特定的生长因子激活时，不仅是器官发生的遗传控制中的一个重要的基本问题。它也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的模式不仅决定了集合系统的结构-它还影响了肾单位的数量，这在人类中是非常可变的，并且被认为影响了肾脏疾病的进展速度和高血压的发展。因此，Pea 3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.