We have promoted the concept of a highly dynamic slit diaphragm protein complex that regulates podocyte foot process formation and maintenance by triggering cell survival, polarity, endocytosis, cytosceletal organization and mechanosensation. The transmembrane immunoglobulin superfamily proteins Nephrin and Neph are highly conserved among species and it recently appeared that Nephrin-Neph protein complexes serve as evolutionary conserved cell recognition modules in Drosophila eye and muscle development, in C.elegans neuronal development and in the formation of the kidney slit diaphragm. We and others could show that Neph1 represents the natural ligand of Nephrin in the slit diaphragm complex. Subsequently, we cloned and identified highly conserved members of the Neph1 protein family which we termed Neph2 and Neph3. The establishment of innovative techniques and models to overcome the difficult accessibility to study podocyte molecules in vivo will be a pacemaker to track molecular functions of slit diaphragm molecules and to identify novel therapeutic targets. Therefore, we are currently combining transgenic mouse models, C. elegans- (cooperation with Dr. Neumann-Haefelin) and Drosophila models (cooperation Prof. Fischbach, Biology, Freiburg) to systematically evaluate Neph- nephrin protein function.