Wnt/β-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75NTR), as a negative regulator of Wnt/β-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/β-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/β-catenin signaling during development.
PurposeThe aim of this study was to investigate the changes of Wnt pathway inhibition on Amacrine and Muller cells in the embryonic period of zebrafish.MethodsZebrafishes divided into two subgroups: control and Wnt signaling pathway inhibited groups. The effect of Wnt inhibition (IWR1) on Amacrine and Müller cells were examined at 24th, 38th, 60th and 72nd hours of Zebrafish embryos. Immunofluorescence imaging and in situ hybridization methods were used to compare the ocular structures of the groups treated with glutamine synthetase, calretinin, Neuro D1 (Amacrine and Muller cell markers), Pax6 and Rx3 (genes effective in eye formation).ResultsThe most striking results of our study are; the diminished overall cellular structures of neuroretina at the 24th, 60th hour with Neuro D1, decreased Phospho‐Beta‐catenin staining at the 24th hour, apoptosis of whole ocular tissues at the 24th hour with Cleaved Caspase 3, no staining with glutamine synthase at the 38th hour, reduced β‐Catenin staining in the 60th hour and increased Caspase 3 staining at 72nd hour in IWR group. The related figures (Fig 1–7) are shown below.ConclusionsThe results of our study revealed that the inhibition of the Wnt/beta‐catenin pathway could be responsible for the maldevelopment of ocular tissues especially on the neuroretinal tissues including Amacrine and Muller cells at the early stages. Our results could shed a light on the pathophysiology of developmental anomalies of ocular tissues like colobomas and be a new model for other experimental researches like retinopathies in the future.
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