Wnt signaling plays crucial roles in development and tissue homeostasis, and its dysregulation leads to various diseases, notably cancer. Wnt/β-catenin signaling is initiated when the glycoprotein Wnt binds to and forms a ternary complex with the Frizzled and low-density lipoprotein receptor-related protein 5/6 (LRP5/6). Despite being identified as a Wnt co-receptor over 20 years ago, the molecular mechanisms governing how LRP6 senses Wnt and transduces downstream signaling cascades are still being deciphered. Due to its role as one of the main Wnt signaling components, the dysregulation or mutation of LRP6 is implicated in several diseases such as cancer, neurodegeneration, metabolic syndrome and skeletal disease. Herein, we will review how LRP6 is activated by Wnt stimulation and explore the various regulatory mechanisms involved. The participation of LRP6 in other signaling pathways will also be discussed. Finally, the relationship between LRP6 dysregulation and disease will be examined in detail.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and behavioral changes. Extracellular deposition of amyloid plaques (Aβ) and intracellular deposition of neurofibrillary tangles in neurons are the major pathogenicities of AD. However, drugs targeting these therapeutic targets are not effective. Therefore, novel targets for the treatment of AD urgently need to be identified. Expression of the mesoderm-specific transcript (Mest) is regulated by genomic imprinting, where only the paternal allele is active for transcription. We identified hypermethylation on the Mest promoter, which led to a reduction in Mest mRNA levels and activation of Wnt signaling in brain tissues of AD patients. Mest knockout (KO) using the CRIPSR/Cas9 system in mouse embryonic stem cells and P19 embryonic carcinoma cells leads to neuronal differentiation arrest. Depletion of Mest in primary hippocampal neurons via lentivirus expressing shMest or inducible KO system causes neurodegeneration. Notably, depletion of Mest in primary cortical neurons of rats leads to tau phosphorylation at the S199 and T231 sites. Overall, our data suggest that hypermethylation of the Mest promoter may cause or facilitate the progression of AD.
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