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Hum Mol Genet. 2010 Jun 15;19(12):2347-59. doi: 10.1093/hmg/ddq108. Epub 2010 Mar 16.

A model organism approach: defining the role of Neph proteins as regulators of neuron and kidney morphogenesis.

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Renal Division, University Hospital Freiburg, D-79106 Freiburg, Germany. H.)/


Mutations of the immunoglobulin superfamily proteins nephrin and Neph1 lead to congenital nephrotic syndrome in humans or mice. Neph proteins are three closely related molecules that are evolutionarily conserved and mediate cell recognition. Their importance for morphogenetic processes including the formation of the kidney filtration barrier in vertebrates and synaptogenesis in Caenorhabditis elegans has recently been uncovered. However, the individual morphogenetic function of mammalian Neph1-3 isoforms remained elusive. We demonstrate now that the Neph/nephrin family proteins can form cell-cell adhesion modules across species. Expression of all three mammalian Neph isoforms partially rescued mutant C. elegans lacking their Neph homolog syg-1 and restored synapse formation, suggesting a functional redundancy between the three isoforms. Strikingly, the rescue of defective synaptic connectivity was prevented by deletion of the highly conserved cytoplasmic PSD95/Dlg/ZO-1-binding motif of SYG-1/Neph proteins, indicating the critical role of this intracellular signaling motif for SYG-1/Neph-dependent morphogenetic events. To determine the significance of Neph isoform redundancy for vertebrate kidney development, we analyzed the expression pattern and the functional role of Neph proteins in zebrafish. In situ hybridizations identified zNeph1 and zNeph2 as glomerular proteins. Morpholino knockdown of either zNeph1 or zNeph2 resulted in loss of slit diaphragms and leakiness of the glomerular filtration barrier. This is the first report utilizing C. elegans to study mammalian Neph/nephrin protein function and to demonstrate a functional overlap of Neph1-3 proteins. Furthermore, we identify Neph2 as a novel critical regulator of glomerular function, indicating that both Neph1 and Neph2 are required for glomerular maintenance and development.

[Indexed for MEDLINE]

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