MOLECULAR EVENTS IN UROGENITAL DEVELOPMENT

肾脏的发育始于输尿管芽侵入肾脏。 后肾间充质，并诱导其改变为上皮细胞 表型然后，诱导的间充质诱导输尿管芽， 分支。这种相互诱导是由一系列已知的， 我们怀疑还有更多未知分子我们计划的主要目的是 来识别在这个过程中至关重要的新分子。 这个PPG的成员已经确定了新的基因， 肾发生，c-ret癌基因及其配体GDNF;当其中任何一个是 删除，肾发育不全发展。同一个小组，由康斯坦丁尼博士 发现一种新基因Axin的突变，Axin是融合蛋白的产物， 小鼠的基因座也会导致严重的肾脏发育不良， 当他们发现这个基因是一个关键的 Wnt途径的一个组成部分，已知这是一个关键的途径， 泌尿生殖发育该PPG的另一位成员最近的一项研究表明， （门德尔松）发现，一种视黄酸受体（RAR β 2）是 在基质细胞中高度表达，该基因的缺失导致 肾发育不全J Barasch博士已经产生了输尿管芽细胞系 其上清液可以拯救间充质细胞免于凋亡， 膜诱导被拯救的间充质转化为肾小管上皮细胞。 他已经从这些上清液中纯化了生长因子， 产生的抑制性单克隆抗体 膜。Al-Awqati博士制造了一种单克隆抗体， 分支形态发生，并已纯化其抗原，膜蛋白 在诱导的间充质中表达，但在成人肾脏中不表达。的cDNA 表明这是一种新的基础蛋白质，可能是另一种蛋白质的受体。 细胞外基质中的蛋白质。另一种抗体抑制 当其抗原被纯化时， 克隆后，发现它在肾小球系膜和平滑肌中表达， 成人中的细胞。 这四位具有互补专业知识的科学家将通过以下方式进行合作： 用遗传学、生物化学和细胞学方法研究其结构 这些新基因的功能及其在形成 肾脏的三维结构。虽然很明显， 先天性肾发育不良必须由这些基因的突变引起， 其他形态发生基因，有证据表明，基因决定 功能肾单位数量的差异可能是 许多种高血压和其他肾脏疾病。因此，我们认为， 肾脏发育早期阶段的研究， 确定的肾单位数量可能具有广泛的临床意义， 影响

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. This reciprocal induction is mediated by a cascade of known and we suspect many more unknown molecules. The major aim of our Program is to identify new molecules that are critical in this process. Members of this PPG have already identified new genes that are critical nephrogenesis, the c-ret oncogene and its ligand GDNF; when either is deleted, renal agenesis develops. The same group, led by Dr. Constantini found that mutation in a new gene termed Axin, the product of the fused locus in mice also leads to severe kidney dysplasia, and much excitement was generated when they discovered that this gene is a critical component of the wnt pathway, a pathway known to be critical for urogenital development. A recent study by another members of this PPG (Mendelsohn) found that one retinoic acid receptor (RAR beta 2) is highly expressed in the stromal cells and deletion of this gene leads to renal agenesis. Dr. J Barasch has produced a ureteric bud cell line whose supernatant can rescue mesenchyme from apoptosis and whose membrane induce the rescued mesenchyme to covert to tubular epithelia. He has already purified growth factors from these supernatants and generated inhibitory monoclonal antibodies against the inducing membranes. Dr. Al-Awqati generated a monoclonal antibody that inhibited branching morphogenesis and has purified its antigen, a membrane protein expressed in induced mesenchyme but not in the adult kidney. The cDNA shows that is a new basal protein likely to be a receptor for another protein in the extracellular matrix. Another antibody inhibited angiogenesis in the developing kidney and when its antigen was purified and cloned, it was found to be expressed in mesangial and smooth muscle cells in the adult. These four scientists with complementary expertise will collaborate by using genetic, biochemical and cellular method 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 at the heart of many kinds of hypertension and perhaps other kidney diseases. Hence, studies of the early stages of kidney development, the stage at which the number of nephrons is determined are likely to have wide clinical implications.