BMP SIGNALLING IN EYE AND KIDNEY DEVELOPMENT

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DESCRIPTION (provided by applicant): Members of the TGF-beta superfamily of secreted growth factors play fundamental roles governing morphogenetic processes throughout development. Our previous studies have shown that Bone Morphogenetic Protein7 (BMP7) is required during ontogeny of the mammalian eye and kidney. Experiments outlined in this renewal application aim to clarify our understanding of BMP functions during kidney development and morphogenesis. We will test the ability of heterologous BMPs to replace BMP7 functions. To evaluate the relative contribution of BMP7 expression in the ureteric epithelium and mesenchyme, we will conditionally inactivate BMP7 in these specific cell types using Cre-lox technology. To investigate the origins and potential interactions between stroma and mesenchyme, we will mark cells in vivo using a binary system. We plan to identify candidate genes responsible for maintenance of the uninduced mesenchyme by transcriptional profiling. Expression domains of BMP and TGF-beta /activin regulated Smads, as well as the inhibitory Smads will be described. We will exploit a conditional allele of Smad1 to selectively delete Smad1 function from the metanephric mesenchyme. To disrupt TGF-beta /BMP signals, transgenic mice expressing Cre in the mesenchyme will also be crossed to animals harboring a conditional Smad4 allele. Signals responsible for down regulation of Smad expression during the mesenchymal/epithelial transition will be analyzed. To evaluate candidate Wnt signals originating from either the newly induced mesenchyme or from the ureteric bud, Smad expression will be assessed in Wnt4 mutant kidney tissue, and in isolated mesenchymes grown on stably transfected fibroblasts expressing selective Wnt proteins. Collectively these experiments should provide insight into TGF-beta signaling pathways in the developing kidney.