These data complement the data already provided in Chen-Plotkin e

These data complement the data already provided in Chen-Plotkin et al. (2008), providing a systems level framework in which to delineate the GRN+ FTD

molecular signature identified using differential expression http://www.selleckchem.com/products/MLN8237.html analysis in the original study. WGCNA allows for separation of distinct factors that may be related to GRN+ FTD, and facilitates the focus on the gene expression changes most relevant to disease pathogenesis. To further explore the relationship of the genes identified in vitro with GRN downregulation in vivo, we analyzed the GRN containing module, the blue module. The blue ME is highly specific to GRN+ FTD affected brain regions (Figure 5B), indicating that genes in this module are specifically upregulated in these brain areas. GO analysis identified Wnt signaling to

be significantly enriched within this module ( Table S6), including canonical Wnt pathway transcription factors LEF1, TCF7L1, and Selleck PF 01367338 TCF7L2. To probe the genes most associated with chronic GRN deficiency in vivo, we again examined the submodule containing GRN within this larger module. Remarkably, this module is centered around two hub genes that are both upregulated in disease ( Figure 5C): Annexin-V (ANXA5), a known mediator of apoptosis ( Vermes et al., 1995), and LRP10, a newly discovered inhibitor of the canonical Wnt signaling pathway ( Jeong et al., 2010). This module also contains FZD2, which is upregulated and negatively correlated with GRN levels in vivo, consistent with the in vitro data. Analysis of these human brain samples revealed that FZD2 is significantly upregulated only in frontal cortex of GRN+ FTD samples, underscoring its potential role in disease pathogenesis. The upregulation of multiple Wnt pathway activating components and downregulation of negative regulators both in vitro and in vivo showed a remarkable degree of consistency. These data not only support the relevance of the Wnt pathway changes observed in cell-culture and in human FTD in vivo, but conversely indicate which of the changes observed in brain are a direct effect

of GRN loss, and are not due to postmortem confounders, such as a change in cell composition (due to inflammation or cell loss) during the neurodegenerative process. We were particularly intrigued by old the consistent upregulation of FZD2, since it is one of the most proximal pathway members, acting as a Wnt receptor ( Chan et al., 1992 and Slusarski et al., 1997). To follow Fzd2 in vivo at a time prior to neuropathological alterations or overt neurodegeneration, we analyzed independent gene expression data from cerebellum, cortex, and hippocampus of 6-week-old GRN knockout mice, at a time point before overt cell loss or neuropathology. This analysis demonstrated only 25 differentially expressed genes in cortex ( Table S7, p < 0.

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