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Binding of sFRP-3 to EGF in the extra-cellular space affects proliferation, differentiation and morphogenetic events
Raffaella Scardigli1, Cesare Gargioli, Daniela Tosoni
1Department of Developmental Biology, Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Rome, Rome, Italy.
Background:
sFRP-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 Findings:
Here 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/Significance:
sFRP-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.
Insights
Soluble Frizzled Related Protein-3 (sFRP-3) and Epidermal Growth Factor (EGF) reciprocally regulate embryonic development by inhibiting each other’s effects on cell proliferation and differentiation.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Signaling
Background:
- sFRP-3 is a soluble antagonist of Wnts, crucial for embryonic development.
- Wnt signaling regulates cell proliferation, differentiation, and organogenesis.
- sFRP-3, a member of the soluble Frizzled Related Protein family, inhibits Wnt signaling pathways.
Purpose of the Study:
- To investigate the interaction between sFRP-3 and Epidermal Growth Factor (EGF).
- To elucidate the roles of sFRP-3 and EGF in embryonic cell proliferation, differentiation, and morphogenesis.
- To understand the reciprocal regulation between sFRP-3 and EGF during embryogenesis.
Main Methods:
- Over-expression and ablation of sFRP-3 in mouse and Xenopus embryos.
- In vitro binding assays to confirm direct interaction between EGF and sFRP-3.
- Analysis of EGF-induced fibroblast proliferation and hair follicle development.
Main Results:
- sFRP-3 specifically blocks EGF-induced fibroblast proliferation and foci formation.
- sFRP-3 over-expression reverses EGF-mediated inhibition of hair follicle development.
- EGF over-expression reverses sFRP-3-induced inhibition of myogenesis and axis truncation.
Conclusions:
- sFRP-3 and EGF exhibit reciprocal inhibitory effects on cell proliferation, differentiation, and morphogenesis.
- These molecules bind to each other, suggesting a novel regulatory mechanism during embryogenesis.
- The findings highlight a cross-talk between Wnt and EGF signaling pathways in embryonic development.
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