Molecular Events in Urogenital Development

当输尿管芽侵入后肾间充质并诱导其转变为上皮表型时，肾脏开始发育。诱导后的间充质诱导输尿管芽分枝。我们计划的主要目标是识别在这一过程中至关重要的新分子。PPG的四个独立成员已经发现了对肾脏形成至关重要的新基因。科斯坦蒂尼博士发现，c-ret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。他最近培育了在输尿管芽中表达绿色荧光蛋白的小鼠，门德尔松博士用这些小鼠来绘制输尿管的三维轨迹 当它向膀胱移动时，它就会萌芽。她发现了一块注定要形成膀胱三角的间充质楔形结构，并发现维甲酸对其分化至关重要。门德尔松还发现了一种新的相互诱导环，通过后肾基质细胞向输尿管芽发出信号，诱导ret的表达，现在他提议研究维甲酸在下尿路形成中的作用。众所周知，孕妇(和其他哺乳动物)的维甲酸缺乏会导致下尿路异常儿童的出生。Barasch博士确定了输尿管芽分泌的长期寻找的分子，以诱导后肾间充质转化为上皮细胞。他最近发现了第二个诱导因素，Lipocalin，这是一种铁运输蛋白，从而确定了细胞中一种全新的铁运输途径。这一途径对肾脏发育至关重要，并针对肾脏形成中的一个单独阶段。Al-Awqati博士发现，后肾间充质含有干细胞，能够生成肾单位的所有上皮细胞。他还证明了位于乳头中的多能干细胞的存在，这些干细胞很可能参与了损伤期间肾脏的修复。这四位拥有互补专业知识的科学家将通过使用遗传学、生化和细胞方法合作，研究这些新基因的结构和功能，以及它们在肾脏三维结构形成中的作用。虽然很明显，先天性肾发育不良肯定是由这些和其他形态发生基因的突变引起的，但有证据表明，基因决定的功能肾单位数量的差异可能是高血压和其他肾脏疾病发展的核心。因此，对肾脏发育早期阶段的研究，也就是确定肾单位数量的阶段，可能具有广泛的临床意义。

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.