Abstract
BackgroundThe Wnt signaling pathway is a cellular communication pathway that plays critical roles in development and disease. A major class of Wnt signaling regulators is the Dickkopf (Dkk) family of secreted glycoproteins. Although the biological properties of Dickkopf 1 (Dkk1) and Dickkopf 2 (Dkk2) are well characterized, little is known about the function of the related Dickkopf 3 (Dkk3) protein in vivo or in cell lines. We recently demonstrated that Dkk3 transcripts are upregulated during photoreceptor death in a mouse model of retinal degeneration. In this study, we characterized the activity of Dkk3 in Wnt signaling and cell death.ResultsDkk3 was localized to Müller glia and retinal ganglion cells in developing and adult mouse retina. Western blotting confirmed that Dkk3 is secreted from Müller glia cells in culture. We demonstrated that Dkk3 potentiated Wnt signaling in Müller glia and HEK293 cells but not in COS7 cells, indicating that it is a cell-type specific regulator of Wnt signaling. This unique Dkk3 activity was blocked by co-expression of Dkk1. Additionally, Dkk3 displayed pro-survival properties by decreasing caspase activation and increasing viability in HEK293 cells exposed to staurosporine and H2O2. In contrast, Dkk3 did not protect COS7 cells from apoptosis.ConclusionThese data demonstrate that Dkk3 is a positive regulator of Wnt signaling, in contrast to its family member Dkk1. Furthermore, Dkk3 protects against apoptosis by reducing caspase activity, suggesting that Dkk3 may play a cytoprotective role in the retina.
Highlights
The Wnt signaling pathway is a cellular communication pathway that plays critical roles in development and disease
These data demonstrate that Dickkopf 3 (Dkk3) is a positive regulator of Wnt signaling, in contrast to its family member Dickkopf 1 (Dkk1)
Dkk3 protects against apoptosis by reducing caspase activity, suggesting that Dkk3 may play a cytoprotective role in the retina
Summary
The Wnt signaling pathway is a cellular communication pathway that plays critical roles in development and disease. A major class of Wnt signaling regulators is the Dickkopf (Dkk) family of secreted glycoproteins. We characterized the activity of Dkk in Wnt signaling and cell death. Wnt ligands are secreted glycoproteins that control a wide range of processes in the developing embryo and in adult tissues. Aberrant Wnt signaling is increasingly being implicated in numerous diseases, including malignancies, Alzheimers disease, retinal degenerations and abnormal development of the eye, limbs and skeleton [1,2,3]. In the absence of Wnt ligands, β-catenin levels are suppressed by the APC-axinGSK3β protein complex via phosphorylation and subsequent degradation by the proteosome [5]. Wnt ligands bind to the cell surface receptors Frizzled and LDL receptor related proteins 5 and 6 (LRP5/6), leading to Disheveled activation and reducing β-catenin degradation. Stabilized β-catenin is transported into the nucleus where it binds to Tcf/Lef type transcription factors and initiates transcription of Wnt target genes
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call