Secreted Frizzled-related proteins can regulate metanephric development

Mech Dev. 2001 Apr;102(1-2):45-55. doi: 10.1016/s0925-4773(01)00282-9.

Abstract

Wnt-4 signaling plays a critical role in kidney development and is associated with the epithelial conversion of the metanephric mesenchyme. Furthermore, secreted Frizzled-related proteins (sFRPs) that can bind Wnts are normally expressed in the developing metanephros, and function in other systems as modulators of Wnt signaling. sfrp-1 is distributed throughout the medullary and cortical stroma in the metanephros, but is absent from condensed mesenchyme and primitive tubular epithelia of the developing nephron where wnt-4 is highly expressed. In contrast, sfrp-2 is expressed in primitive tubules. To determine their role in kidney development, recombinant sFRP-1, sFRP-2 or combinations of both were applied to cultures of 13-dpc rat metanephroi. Both tubule formation and bud branching were markedly inhibited by sFRP-1, but concurrent sFRP-2 treatment restored some tubular differentiation and bud branching. sFRP-2 itself showed no effect on cultures of metanephroi. In cultures of isolated, induced rat metanephric mesenchymes, sFRP-1 blocked events associated with epithelial conversion (tubulogenesis and expression of lim-1, sfrp-2 and E-cadherin); however, it had no demonstrable effect on early events (compaction of mesenchyme and expression of wt1). As shown 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 inappropriate development within differentiated areas of the medulla or in maintaining a population of cortical blastemal cells to facilitate further renal expansion. On the other hand, sFRP-2 might promote tubule formation by permitting Wnt-4 signaling in the presence of sFRP-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / biosynthesis
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • DNA / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Epithelium / metabolism
  • Frizzled Receptors
  • Gene Expression Regulation, Developmental*
  • Homeodomain Proteins / biosynthesis
  • Immunoblotting
  • Immunohistochemistry
  • In Situ Hybridization
  • Kidney / embryology
  • Kidney Tubules / embryology
  • LIM-Homeodomain Proteins
  • Membrane Proteins*
  • Mesoderm / metabolism
  • Mice
  • Nephrons / embryology
  • Protein Binding
  • Protein Biosynthesis
  • Proteins / physiology*
  • Proto-Oncogene Proteins / physiology*
  • Rats
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Time Factors
  • Transcription Factors
  • Wnt Proteins
  • Wnt4 Protein

Substances

  • Cadherins
  • Frizzled Receptors
  • Homeodomain Proteins
  • LIM-Homeodomain Proteins
  • Lhx1 protein, mouse
  • Lhx1 protein, rat
  • Membrane Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Sfrp2 protein, mouse
  • Transcription Factors
  • WD repeat containing planar cell polarity effector
  • Wnt Proteins
  • Wnt4 Protein
  • Wnt4 protein, mouse
  • Wnt4 protein, rat
  • DNA