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Glycogen Synthase Kinase-3 Inactivation and Stabilization of -Catenin Induce Nephron Differentiation in Isolated Mouse and Rat Kidney Mesenchymes

Satu Kuure^*, Anna Popsueva^*, Madis Jakobson^*,, Kirsi Sainio^* and Hannu Sariola^*,

^* Biochemistry and Developmental Biology, Institute of Biomedicine, University of Helsinki, and HusLab, Peadiatric Pathology, Helsinki University Central Hospital, Helsinki, Finland; and Department of Developmental Biology, Institute of Zoology and Hydrobiology, University of Tartu, Tartu, Estonia

Address correspondence to: Dr. Hannu Sariola, Biochemistry and Developmental Biology, Institute of Biomedicine, PO Box 63, Haartmaninkatu 8, University of Helsinki, FIN-00014, Finland. Phone: +358-9-1912-5140; fax: +358-9-1912-5235; E-mail: hannu.sariola{at}helsinki.fi

Received for publication November 6, 2006. Accepted for publication January 17, 2007.

Wnt proteins are required for induction of nephrons in mouse metanephric kidneys, but the downstream pathways that mediate tubule induction and epithelial differentiation have remained obscure. The intracellular mechanisms by which Wnt signaling mediates nephron induction in embryonic kidney mesenchymes were studied. First is shown that transient exposure of isolated kidney mesenchymes to structurally different glycogen synthase kinase-3 (GSK3) inhibitors lithium or 6-bromoindirubin-3'-oxime results in abundant epithelial differentiation and full segregation of nephrons. Shown further by mice with genetically disrupted ureteric bud or Wolffian duct development is that this nephrogenic competence arises independent of the influence of Wolffian duct–derived epithelia. Analysis of the intracellular signaling cascades downstream of GSK3 inhibition revealed stabilization of -catenin and upregulation of Lef1 and Tcf1, both events that are associated with the active canonical Wnt signaling. Last, genetic evidence that metanephric mesenchyme–specific stabilization of -catenin is sufficient to induce nephron differentiation in isolated kidney mesenchymes, similar to that induced by GSK3 inhibitors, is provided. These data show that activation of canonical Wnt pathway is sufficient to induce nephrogenesis and suggest that this pathway mediates the nephron induction in murine kidney mesenchymes.

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