[대학원 생명과학과 세미나 안내]
연사 : 조익훈 교수(서울시립대 생명과학과)
연제 : How does dysregulation of Wnt signaling lead to neuronal degeneration
일시 : 2022년 03월 11일 (금) 오후 4시 30분
장소 : 대면(207호 화상회의실) 및 온라인 화상 강의로 진행됩니다.
초청교수 : 송현규 교수
Abstract
It is well known that β-catenin is a key mediator of Wnt signaling for the regulation of target gene expression. However, we found that transcription factor EB (TFEB) is required for the expression of about 27% of genes that are increased by the treatment of Wnt3a. TFEB is a well-known master regulator of lysosomal biogenesis and autophagy. Under nutrient deprivation condition, TFEB migrates into nucleus and stimulate expression of lysosomal genes. We found that the target genes whose expressions are regulated by Wnt/TFEB are different from the genes that are involved in lysosomal biogenesis. More data for the regulation of TFEB nuclear localization and activation of target genes will be discussed. If our data are really true, the terminology “Wnt/β-catenin signaling” should be changed to “Wnt/β-catenin-TFEB signaling”.
The expression of mesoderm-specific transcript (Mest) is regulated by genomic imprinting where only the paternal allele is active for transcription. Mest is a candidate gene for Silver-Russell Syndrome, and hypermethylation of Mest promoter is associated with oligozoospermia. In addition, Loss of imprinting (LOI) is often associated with various neurodegenerative diseases and cancers. Since aberrant Mest hypermethylation and LOI are implicated in various diseases, it is vital to study Mest promoter hypermethylation and its functional role in AD patients. We found that Mest promoter is hypermethylated, which led to the reduction of Mest mRNA levels and activation of Wnt signaling in the brain tissues of AD patients. Mest KO in both embryonic carcinoma and mouse embryonic stem cells leads to neuronal differentiation arrest. Depletion of Mest in primary hippocampal neurons via lentivirus expressing sh-Mest or inducible KO system caused neurodegeneration. Notably, depletion of Mest in rat primary cortical neurons leads to tau phosphorylation at S199 and T231 sites. Our study has unfolded the epigenetic modification; Mest promoter hypermethylation in AD. Biochemically, we have linked this with Wnt signaling activation and Tau phosphorylation in neurons.