Molecular Events in Urogenital Development

当输尿管芽侵入后肾间质并诱导其转变为上皮表型时，肾脏的发育开始。然后，诱导的间质诱导输尿管芽形成分支。我们项目的主要目的是确定在这一过程中起关键作用的新分子。该PPG的四个独立成员已经确定了对肾脏发生至关重要的新基因。Costantini博士发现c-ret致癌基因或其配体GDNF的缺失会导致肾脏发育不全。他现在正在识别ret诱导输尿管芽分支的下游信号。他最近培育出在输尿管芽中表达GFP的老鼠，Mendelsohn博士用它来绘制输尿管的三维轨迹

Development of the kidney begins when the ureteric bud invades the metanephric mesenchyme and induces it to change to an epithelial phenotype. The induced mesenchyme then induces the ureteric bud to branch. The major aim of our Program is to identify new molecules that are critical in this process. The four independent members of this PPG have already identified new genes critical to nephrogenesis. Dr Costantini discovered that deletion of the c-ret oncogene or its ligand GDNF causes renal agenesis. He is now identifying the down stream signals by which ret induces ureteric bud branching. He recently generated mice which express GFP in the ureteric bud that were used by Dr Mendelsohn to map the three-dimensional trajectory of the ureteric bud as it travels towards the bladder. She identified a wedge of mesenchyme destined to form the bladder trigone and found that retinoids are critical for its differentiation. Mendelsohn also identified a new reciprocal induction loop whereby metanephric stromal cells signal the ureteric bud to induce expression of ret and is now proposing to examine the role of retinoids in the formation of the lower urinary tract. It is well known that retinoid deficiency in pregnant women (and other mammals) results in the birth of children with lower urinary tract anomalies. Dr Barasch identified the long sought molecule that the ureteric bud secretes to induce the conversion of metanephric mesenchyme to epithelia. He recently discovered a second inducing factor, lipocalin that is an iron transport protein thereby identifying a completely new iron transport pathway in cells. This pathway is critical for kidney development and targets a separate stage in nephrogenesis. Dr A1-Awqati discovered that the metanephric mesenchyme contains stem cells capable of generating all the epithelial cells of the nephron. He also demonstrated the existence of pluripotent stem cells located in the papilla, which are likely to be involved in the repair of the kidney during injury. These four scientists with complementary expertise will collaborate by using genetic, biochemical and cellular methods to examine the structure and function of these new genes and their role in the formation of the three dimensional architecture of the kidney. While it is obvious that congenital renal dysplasias must be caused by mutations in these and other morphogenetic genes, there is evidence that genetically determined differences in the number of functioning nephrons might be central to the development of hypertension and other kidney diseases. Hence, studies of the early stages of kidney development, the stage at which the number ofnephrons is determined are likely to have wide clinical implications.