THE FUNCTIONAL ROLE OF SIX2 IN KIDNEY TUBULOGENESIS

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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.