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doi: 10.1242/10.1242/dev.00478
DEVELOPMENT AND DISEASE |
1 Program in Developmental Biology, Research Institute, The Hospital for Sick
Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
2 Division of Nephrology, Department of Paediatrics, University of Toronto, 555
University Avenue, Toronto, Ontario M5G 1X8, Canada
* Author for correspondence (e-mail: norman.rosenblum{at}sickkids.ca)
Accepted 13 March 2003
Renal dysplasia, the most frequent cause of childhood renal failure in humans, arises from perturbations in a complex series of morphogenetic events during embryonic renal development. The molecular pathogenesis of renal dysplasia is largely undefined. While investigating the role of a BMP-dependent pathway that inhibits branching morphogenesis in vitro, we generated a novel model of renal dysplasia in a transgenic (Tg) model of ALK3receptor signaling. We report the renal phenotype, and our discovery of molecular interactions between effectors in the BMP and WNT signaling pathways in dysplastic kidney tissue. Expression of the constitutively active ALK3 receptor ALK3QD, in two independent transgenic lines caused renal aplasia/severe dysgenesis in 1.5% and 8.4% of hemizygous and homozygous Tg mice, respectively, and renal medullary cystic dysplasia in 49% and 74% of hemizygous and homozygous Tg mice, respectively. The dysplastic phenotype, which included a decreased number of medullary collecting ducts, increased medullary mesenchyme, collecting duct cysts and decreased cortical thickness, was apparent by E18.5. We investigated the pathogenesis of dysplasia in these mice, and demonstrated a 30% decrease in branching morphogenesis at E13.5 before the appearance of histopathogical features of dysplasia, and the formation of ß-catenin/SMAD1/SMAD4 molecular complexes in dysplastic renal tissue. Increased transcriptional activity of a ß-catenin reporter gene in ALK3QD;Tcf-gal mice demonstrated functional cooperativity between the ALK3 and ß-catenin-dependent signaling pathways in kidney tissue. Together with our results in the dysplastic mouse kidney, our findings that phospho-SMAD1 and ß-catenin are overexpressed in human fetal dysplastic renal tissue suggest that dysregulation of these signaling effectors is pathogenic in human renal dysplasia. Our work provides novel insights into the role that crucial developmental signaling pathways may play during the genesis of malformed renal tissue elements.
Key words: Renal dysplasia, ALK3, SMAD1, ß-catenin, Signaling
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