Secreted Frizzled-related proteins can regulate metanephric development

Wnt-4 signaling plays a critical role in kidney development and is associat ed with the epithelial conversion of the metanephric mesenchyme. Furthermor e, secreted Frizzled-related proteins (sFRPs) that can bind Wnts are normal ly expressed in the developing metanephros, and function in other systems a s modulators of Wnt signaling. sfrp-1 is distributed throughout the medulla ry and cortical stroma in the metanephros, but is absent from condensed mes enchyme and primitive tubular epithelia of the developing nephron where wnt -1 is highly expressed. In contrast, sfrp-2 is expressed in primitive tubul es. To determine their role in kidney development, recombinant sFRP-1, sFRP -2 or combinations of both were applied to cultures of 13-dpc rat metanephr oi. Both tubule formation and bud branching were markedly inhibited by sFRP -1, but concurrent sFRP-2 treatment restored some tubular differentiation a nd bud branching, sFRP-2 itself showed no effect on cultures of metanephroi . In cultures of isolated, induced rat metanephric mesenchymes, sFRP-1 bloc ked events associated with epithelial conversion (tubulogenesis and express ion of lim-1, sfrp-2 and E-cadherin); however, it had no demonstrable effec t on early events (compaction of mesenchyme and expression of wt1). As show n herein, sFRP-1 binds Wnt-4 with considerable avidity and inhibits the DNA -binding activity of TCF, an effector of Wnt signaling, while sFRP 2 had no effect on TCF activation. These observations suggest that sFRP-1 and sFRP- 2 compete locally to regulate Wnt signaling during renal organogenesis. The antagonistic effect of sFRP-1 may be important either in preventing inappr opriate development within differentiated areas of the medulla or in mainta ining a population of cortical blastemal cells to facilitate further renal expansion. On the other hand, sFRP-2 might promote tubule formation by perm itting Wnt-4 signaling in the presence of sFRP-1. Published by Elsevier Sci ence Ireland Ltd.