Vangl2 promotes the formation of long cytonemes to enable distant Wnt/β-catenin signaling.
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ABSTRACT:
SUBMITTER: Brunt L
PROVIDER: S-EPMC8024337 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2-/- mouse brains, induced cell cycle arrest at the G1/S checkpoint, and decreased the stability of β-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized β-catenin by inhibiting its degradation via the Akt/GSK3β signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the β-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2-/- microglia and/or in Trem2-/- mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/β-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.SIGNIFICANCE STATEMENT Mutations in the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) gene are associated with increased risk for Alzheimer's disease (AD) with effective sizes comparable to that of the apolipoprotein E (APOE) ε4 allele, making it imperative to understand the molecular pathway(s) underlying TREM2 function in microglia. Our findings shed new light on the relationship between TREM2/DNAX-activating protein 12 (DAP12) signaling and Wnt/β-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis. We demonstrate that TREM2 promotes microglial survival by activating the Wnt/β-catenin signaling pathway and that it is possible to restore Wnt/β-catenin signaling when TREM2 activity is disrupted or reduced. Therefore, we demonstrate the potential for manipulating the TREM2/β-catenin signaling pathway for the treatment of AD.
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Project description:BackgroundPorcupine O-acyltransferase (PORCN), a membrane-bound O-acyltransferase, is crucial in Wnt ligand palmitoylation. However, the roles of PORCN in the development of hepatocellular carcinoma (HCC) remain unknown.MethodsWestern blot, real-time quantitative polymerase chain reaction (RT-qPCR) assays, and The Cancer Genome Atlas (TCGA) database were used to study the expression and prognostic values of PORCN in patients with HCC. Following this, Cell Counting Kit-8 (CCK-8), wound-healing tests, Transwell assay, and a xenograft mouse model were employed to examine the effect of PORCN on HCC cells. Finally, the underlying molecular mechanisms involved in cell proliferation and migration caused by PORCN were identified.ResultsThe protein and messenger RNA (mRNA) levels of PORCN in HCC tissues were higher than those of adjacent normal tissues. The analysis of TCGA database indicated that patients with higher PORCN expression had a lower overall survival (OS) rate. Overexpression of PORCN could promote the proliferation and migration abilities of HCC cells both in vitro and in vivo. Gene set enrichment analysis (GSEA) showed that the effect of PORCN on the biological characteristics of HCC cells mainly centered on the Wnt-β-catenin signaling pathway. Mechanically, immunofluorescence staining and subcellular protein fraction assays showed that PORCN could induce epithelial-mesenchymal transition (EMT) by promoting the translocation of β-catenin from the cytoplasm to nucleus, ultimately promoting the progression of HCC.ConclusionsThe findings of this study suggest that PORCN can promote HCC cell proliferation and migration by stimulating the Wnt-β-catenin signaling pathway. Therefore, PORCN may be a promising therapeutic target for HCC.
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