Glycogen Synthase Kinase-3 Alpha Beta Research Articles

Inhibition of GSK3 Represses the Expression of Retinoic Acid Synthetic Enzyme ALDH1A2 via Wnt/β-Catenin Signaling in WiT49 Cells.

Organogenesis, including renal development, requires an appropriate retinoic acid concentration, which is established by differential expression of aldehyde dehydrogenase 1 family member A2 (ALDH1A2) and cytochrome P450 family 26 subfamily A/B/C member 1 (CYP26A1/B1/C1). In the fetal kidney, ALDH1A2 expresses in the developing stroma and renal vesicle and its derivatives but does not present in the ureteric bud. It remains unclear what may contribute to this expression pattern. Here we show that the glycogen synthase kinase 3 alpha/beta (GSK3A/B) inhibitor CHIR99021 significantly represses ALDH1A2 expression in WiT49, which is a Wilms’ tumor cell line that exhibits “triphasic” differential potential and is used as a fetal kidney cell model. CHIR99021 fails to suppress ALDH1A2 as β-catenin is inhibited, suggesting that the downregulation of ALDH1A2 by CHIR99021 is through Wnt/β-catenin signaling. Ectopic expression of mouse Wnt1, Wnt3a, Wnt4, and Wnt9b represses ALDH1A2 expression in WiT49 cells. Using immunohistochemistry, we show an inverse correlation of Aldh1a2 expression with β-catenin in rat E18.5 kidney. ChIP demonstrated that β-catenin is recruited to the ALDH1A2 promoter, the conserved intron1G, and another site within intron 1 of ALDH1A2. Using a luciferase assay, we further show that the ALDH1A2 promoter and the intron1G element are involved in the repression of ALDH1A2 expression by CHIR99021. Our work demonstrates that ALDH1A2 expression can be directly repressed by the Wnt/β-catenin signaling in fetal kidney cells, suggesting that Wnt/β-catenin may play a role in maintaining the expression pattern of ALDH1A2 in the fetal kidney, thus controlling the availability and localization of retinoic acid and regulating aspects of kidney development.

Increased tau phosphorylation on mitogen-activated protein kinase consensus sites and cognitive decline in transgenic models for Alzheimer's disease and FTDP-17: evidence for distinct molecular processes underlying tau abnormalities.

Abnormal tau phosphorylation occurs in several neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here, we compare mechanisms of tau phosphorylation in mouse models of FTDP-17 and AD. Mice expressing a mutated form of human tau associated with FTDP-17 (tau(V337M)) showed age-related increases in exogenous tau phosphorylation in the absence of increased activation status of a number of kinases known to phosphorylate tau in vitro. In a "combined" model, expressing both tau(V337M) and the familial amyloid precursor protein AD mutation APP(V717I) in a CT100 fragment, age-dependent tau phosphorylation occurred at the same sites and was significantly augmented compared to "single" tau(V337M) mice. These effects were concomitant with increased activation status of mitogen-activated protein kinase (MAPK) family members (extracellular regulated kinases 1 and 2, p38, and c-Jun NH(2)-terminal kinase) but not glycogen synthase kinase-3alphabeta or cyclin-dependent kinase 5. The increase in MAPK activation was a discrete effect of APP(V717I)-CT100 transgene expression as near identical changes were observed in single APP(V717I)-CT100 mice. Age-dependent deficits in memory were also associated with tau(V337M) and APP(V717I)-CT100 expression. The data reveal distinct routes to abnormal tau phosphorylation in models of AD and FTDP-17 and suggest that in AD, tau irregularities may be linked to processing of APP C-terminal fragments via specific effects on MAPK activation status.