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BMP Receptor ALK3 Controls Collecting System Development

Sunny Hartwig^*,, Darren Bridgewater^*, Valeria Di Giovanni^*,, Jason Cain^*, Yuji Mishina^¶ and Norman D. Rosenblum^*,,,,||

^* Program in Developmental Biology and Division of Nephrology, The Hospital for Sick Children, Toronto; Departments of Physiology, and Laboratory Medicine and Pathobiology and ^|| Department of Pediatrics, University of Toronto, Canada; and the ^¶ Molecular Developmental Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institutes of Health, Bethesda, Maryland

Correspondence: Dr. Norman Rosenblum, Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Phone: 416-813-5667; Fax: 416-813-5252; E-mail: norman.rosenblum{at}sickkids.ca

Received for publication January 21, 2007. Accepted for publication August 6, 2007.

The molecular signals that regulate growth and branching of the ureteric bud during formation of the renal collecting system are largely undefined. Members of the bone morphogenetic protein (BMP) family signal through the type I BMP receptor ALK3 to inhibit ureteric bud and collecting duct cell morphogenesis in vitro. We investigated the function of the BMP signaling pathway in vivo by generating a murine model of ALK3 deficiency restricted to the ureteric bud lineage (Alk3^UB–/– mice). At the onset of branching morphogenesis, Alk3^UB–/– kidneys are characterized by an abnormal primary (1°) ureteric bud branch pattern and an increased number of ureteric bud branches. However, during later stages of renal development, Alk3^UB–/– kidneys have fewer ureteric bud branches and collecting ducts than wild-type kidneys. Postnatal Alk3^UB–/– mice exhibit a dysplastic renal phenotype characterized by hypoplasia of the renal medulla, a decreased number of medullary collecting ducts, and abnormal expression of β-catenin and c-MYC in medullary tubules. In summary, normal kidney development requires ALK3-dependent BMP signaling, which controls ureteric bud branching.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673