Gene Expression Profiling in Cells with Enhanced ?-Secretase Activity

Magold, Alexandra I.; Cacquevel, Matthias; Fraering, Patrick C.

TERA, a gene that we found to be decreased in transcription (down by 23.5-fold), has been connected to brain development and Wnt antagonism as well. TERA is decreased to minimal transcript levels with enhanced c-secretase activity (Fig. 3) . This gene, encoding a phosphoprotein of unknown function, is upregulated in squamous cell carcinoma (SCC), adenocarcinoma (AC), and colon, ovary, rectum and stomach tumors [54] (suggesting associations with Notch?). It has also been reported that TERA gene expression is increased in day 13 embryonic (E13) and decreased in E17 cortex and maintains low, but consistent expression levels in the subventricular zone (SVZ) [55] . The expression pattern in earlier rather than later stages of brain development and in the location of neuronal stem cell niches, like the SVZ, suggest possible roles for Tera in regenerative processes and raise questions about its function if the gene is being shut down in degenerative disorders like AD [55] . Tera expression has further been found to be maintained in neural progenitors and downregulated during non-neural differentiation, and was shown to have appreciable expression in embryonic stem cells in a screen Figure 6 . Involvement of c-secretase-dependently transcribed genes in Wnt pathways. Several key players of the canonical Wnt pathway (green panel) were reported by our microarray to increase (red quadrangles) or decrease (blue quadrangles) in transcript levels under conditions of enhanced c-secretase activity compared to inhibited activity. b-Catenin is a central node connecting Wnt-Frizzled-Dishevelled to a downstream effect influencing the cell cycle (see also Fig. 4 and interactions of encoded proteins). For better understanding, selected genes that were not detected by the microarray are displayed as well (dashed lines black quadrangles). CycD was reported to be regulated by PTPRG, one of the top scoring candidates for c-secretase affected gene transcription. Nkd, which we found to be increased in transcript levels, connects the canonical Wnt pathway with the planar cell polarity pathway (blue panel). CD44, a well-known c-secretase substrate, interacts with SPP1. SPP1 and UPP1, two strong candidates are both under the control of the same transcription factor Oct3/4, as has been suggested for TERA [92] . UPP1 directly interacts with Vimentin (see also Fig. 4) , a known player in AD and a cytoskeletal protein. Crucial genes of the Wnt/Ca 2+ pathway (grey panel) were also found to be differentially expressed in our array. All together, c-secretase activity influences the transcript levels of genes of the canonical, the planar cell polarity and Ca 2+ Wnt pathways. doi:10.1371/journal.pone.0006952.g006 for functional genes in ES cells that implicated Wnt antagonism in neural differentiation [56] .