THE FUNCTIONAL ROLE OF SIX2 IN KIDNEY TUBULOGENESIS

描述（由申请人提供）：肾脏是一个很好的模型，通过使用专门为该器官开发的现有培养系统来研究体内和体外组织相互作用。在哺乳动物肾脏发育过程中，输尿管芽上皮向周围的后肾间质提供诱导信号。这些信号促进输尿管芽尖周围的间充质细胞凝聚，形成小管前凝聚物，上皮化后形成简单上皮小管。然后小管上皮经历增殖和分化，产生不同节段的分泌肾单位，这是成人肾脏的功能单位。相互的后肾间充质信号似乎是促进输尿管芽分支的必要条件。我们最近对同型盒基因Six2的失活表明，该基因的功能对肾脏器官发生至关重要。我们的初步研究表明，Six2活性在导致肾元分化的多步骤过程中是必需的，最有可能维持后肾间充质祖细胞/干细胞库处于未分化状态。我们的长期目标是通过使用Six2作为切入点来描述和阐明在发育中的肾脏中介导小管形成的分子事件，并确定Six2和Wnt信号通路之间可能的直接调节相互作用。

DESCRIPTION (provided by applicant): The kidney is a great model in which to study tissue interactions in vivo and in vitro by the use of the available culture systems developed specifically for this organ. During mammalian kidney development, inductive signals are provided by the ureteric bud epithelium to the surrounding metanephric mesenchyme. These signals promote the condensation of mesenchymal cells around the tips of the ureteric buds leading to the formation of pretubular condensates, which following epithelialization will form simple epithelial tubules. Tubular epithelium then undergoes proliferation and differentiation to give rise to the different segments of the secretory nephrons, the functional unit of the adult kidney. Reciprocal metanephric mesenchymal signals appear to be required to promote ureteric bud branching. Our recent inactivation of the homeobox gene Six2 demonstrated that this gene function is crucial for kidney organogenesis. Our initial studies suggested that Six2 activity is required during the multistep process leading to nephron differentiation, most likely to maintain a pool of metanephric mesenchymal progenitor/stem cells in an undifferentiated state. Our long-term objective is to characterize and elucidate the molecular events mediating tubulogenesis in the developing kidney by using Six2 as an entry point and to identify possible direct regulatory interactions between Six2 and the Wnt signaling pathway.