Presenilin 1 mediates retinoic acid‐induced differentiation of SH‐SY5Y cells through facilitation of Wnt signaling

Presenilin 1 interacts with β‐catenin, an essential component of the Wnt signaling pathway. To elucidate the role of presenilin 1‐β‐catenin interaction in neuronal differentiation, we established SH‐SY5Y cells stably expressing wild‐type presenilin 1, P117L mutant presenilin 1, which is linked to the early‐onset familial form of Alzheimer's disease, and D385A mutant presenilin 1, which has no aspartyl proteinase activity. We demonstrate that SH‐SY5Y cells stably expressing D385A mutant presenilin 1 failed to differentiate in response to retinoic acid treatment. Retinoic acid caused an increase in nuclear β‐catenin levels in SH‐SY5Y cells, which was followed by an increase in cyclin D1 protein levels. Abnormal cellular accumulation of β‐catenin was observed in D385A mutant transfected cells, whereas nuclear β‐catenin and cellular cyclin D1 levels failed to increase. Conversely, SH‐SY5Y cells expressing the P117L mutant differentiated normally and showed increased nuclear β‐catenin and cellular cyclin D1 levels. These findings suggest that neuronal differentiation of SH‐SY5Y cells involves the Wnt signaling pathway and that presenilin 1 plays a crucial role in Wnt signal transduction by regulating the nuclear translocation of β‐catenin. © 2003 Wiley‐Liss, Inc.