Secreted Frizzled-related proteins can regulate metanephric development.
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.
Yoshino
K
K
Laboratory of Comparative Carcinogenesis, Building 538/Room 205E, National Cancer Institute, Frederick, MD 21702, USA. yoshino@mail.ncifcrf.gov
Rubin
J S
JS
Higinbotham
K G
KG
Uren
A
A
Anest
V
V
Plisov
S Y
SY
Perantoni
A O
AO
D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000378:metabolism; D051157:Frizzled Receptors; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000096:biosynthesis; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000196:embryology; D007684:Kidney Tubules / Q000196:embryology; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009399:Nephrons / Q000196:embryology; D011485:Protein Binding; D014176:Protein Biosynthesis; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D060528:Wnt4 Protein; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
D015820:Cadherins; D004247:DNA; D051157:Frizzled Receptors; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D060528:Wnt4 Protein; D000099274:Frizzled-Related Proteins; C499523:Lhx1 protein, mouse; C499522:Lhx1 protein, rat; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C555582:Wnt4 protein, mouse; C555583:Wnt4 protein, rat