Abstract
BackgroundsFRP-3 is a soluble antagonist of Wnts, widely expressed in developing embryos. The Wnt gene family comprises cysteine-rich secreted ligands that regulate cell proliferation, differentiation, organogenesis and oncogenesis of different organisms ranging from worms to mammals. In the canonical signal transduction pathway Wnt proteins bind to the extracellular domain of Frizzled receptors and consequently recruit Dishevelled (Dsh) to the cell membrane. In addition to Wnt membrane receptors belonging to the Frizzled family, several other molecules have been described which share homology in the CRD domain and lack the putative trans-membrane domain, such as sFRP molecules (soluble Frizzled Related Protein). Among them, sFRP-3 was originally isolated from bovine articular cartilage and also as a component of the Spemann organizer. sFRP-3 blocks Wnt-8 induced axis duplication in Xenopus embryos and binds to the surface of cells expressing a membrane-anchored form of Wnt-1. Injection of sFRP-3 mRNA blocks expression of XMyoD mRNA and leads to embryos with enlarged heads and shortened trunks.Methodology/Principal FindingsHere we report that sFRP-3 specifically blocks EGF-induced fibroblast proliferation and foci formation. Over-expression of sFRP-3 reverts EGF-mediated inhibition of hair follicle development in the mouse ectoderm while its ablation in Xenopus maintains EGF-mediated inhibition of ectoderm differentiation. Conversely, over-expression of EGF reverts the inhibition of somitic myogenesis and axis truncation in Xenopus and mouse embryos caused by sFRP-3. In vitro experiments demonstrated a direct binding of EGF to sFRP-3 both on heparin and on the surface of CHO cells where the molecule had been membrane anchored.Conclusions/SignificancesFRP-3 and EGF reciprocally inhibit their effects on cell proliferation, differentiation and morphogenesis and indeed are expressed in contiguous domains of the embryo, suggesting that in addition to their canonical ligands (Wnt and EGF receptor, respectively) these molecules bind to each other and regulate their activities during embryogenesis.
Highlights
The Wnt gene family comprises cysteine-rich secreted ligands that regulate cell proliferation, differentiation, organogenesis and oncogenesis of different organisms ranging from worms to mammals [1,2]
In addition to Frizzled receptors, four sFRP (Soluble Frizzled Related Protein), sharing homology in the cystein rich domain (CRD) domain but lacking the putative trans-membrane domain have been identified [6]. sFRP-3, known as Frzb-1, was originally isolated from bovine articular cartilage and as a component of the Spemann organizer [7]. sFRP-3 binds to the surface of cells
Since proliferation depends upon the action of different mitogens present in the fetal calf serum (FCS), such as EGF, FGF, PDGF, we investigated whether sFRP-3 could block the mitogenic response mediated by any of these factors
Summary
The Wnt gene family comprises cysteine-rich secreted ligands that regulate cell proliferation, differentiation, organogenesis and oncogenesis of different organisms ranging from worms to mammals [1,2]. In addition to Frizzled receptors, four sFRP (Soluble Frizzled Related Protein), sharing homology in the CRD domain but lacking the putative trans-membrane domain have been identified [6]. PLoS ONE | www.plosone.org sFRP-3-EGF Antagonism expressing a membrane-anchored form of Wnt-1 and blocks Wnt induced axis duplication in Xenopus embryos [8]. In addition to Wnt membrane receptors belonging to the Frizzled family, several other molecules have been described which share homology in the CRD domain and lack the putative trans-membrane domain, such as sFRP molecules (soluble Frizzled Related Protein). SFRP-3 blocks Wnt-8 induced axis duplication in Xenopus embryos and binds to the surface of cells expressing a membrane-anchored form of Wnt-1. Injection of sFRP-3 mRNA blocks expression of XMyoD mRNA and leads to embryos with enlarged heads and shortened trunks
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