Presenilin-1 and TCF/beta-catenin signaling: Effects on neuronal differentiation

Wnt signaling plays a critical role in development. One of the ways by which this signal transduction pathway specifies cell fate is by regulating the expression of specific target genes through the activation of TCF/β-catenin mediated transcription by either binding to coactivators CBP or p300. When β-catenin is bound to CBP, this TCF/β-catenin/CBP complex is involved in transcription of genes involved in proliferation. Usage of p300 coactivator results in transcription of genes that are critical for differentiation.; Mutations in presenilin-1 (PS-1), a transmembrane protein that exhibits ysecretase activity, have been shown to be associated with the early-onset inherited forms of Alzheimer's disease (AD). Mutant PS-l, PS-1/L286V, causes a dramatic increase in TCF/β-catenin mediated transcription in PC-12 cells, which prevents normal nerve growth factor (NGF) induced neuronal differentiation and neurite outgrowth. Selective inhibition of TCF/β-catenin/CBP mediated transcription with the small molecule antagonist PNRI-001 corrects these defects in neuronal differentiation, highlighting the importance of TCF/β-catenin mediated signaling in this process. We presented evidence that in PC-12 cell model system, there is increased proteolysis of p35, an interacting partner of CDK-5, to p25, as a result of this PS-1 mutation. Crosstalk between TCF/β-catenin mediated signaling and the CDK-5 pathway was also demonstrated.; The research contained herein, increases our understanding of the role that TCF/β-catenin mediated signaling plays during neuronal differentiation. Additionally, this research provides a novel molecular framework to connect p35 or p25/CDK-5 with the TCF/β-catenin mediated signaling pathway.