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Wnt/beta-catenin signaling has been shown to promote self-renewal in a variety of tissue stem cells, including neuronal stem cells and hematopoietic stem cells. However, activation of the Wnt/beta-catenin pathway promoted and inhibition of the pathway prevented differentiation of neuronal precursor cells. A clear explanation for the differential effects of Wnt/beta-catenin activation on neuronal precursors is not available at present. Presenilin-1 (PS-1) is a polytopic protein comprised of six to eight transmembrane domains. PS-1, as part of the gamma-secretase complex, is required for the intramembrane proteolysis of both amyloid precursor protein (APP) and Notch. Additionally, through interactions with beta-catenin, PS-1 is associated with modulation of Wnt/beta-catenin signaling. A familial Alzheimer's disease-associated PS-1 mutant, PS-1(L286V), causes a dramatic increase in T cell factor (TCF)/beta-catenin transcription in PC-12 cells, which prevents normal nerve growth factor (NGF)-induced neuronal differentiation and neurite outgrowth. Selective inhibition of TCF/beta-catenin/cAMP-response element-binding protein (CREB)-binding protein (CBP)-mediated transcription, but not TCF/beta-catenin/p300, with the recently described small molecule antagonist ICG-001 corrects these defects in neuronal differentiation, highlighting the importance of Wnt/beta-catenin signaling in this process. We propose that increased TCF/beta-catenin/CBP-mediated transcription, as well as a failure to switch to TCF/beta-catenin/p300-mediated transcription, play an important role in decreasing neuronal differentiation.
Teo et al. (Wed,) studied this question.