, 2001, Lie et al., 2005, Willert et al., 2003 and You et al., 2002). Further, disease onset and rate of progression may correlate with endogenous baseline activity of neuroprotection provided by the Wnt signaling pathway ( De Ferrari et al., 2007). The manipulation of FZD2 and other members of its pathway selleck is thus a potential therapeutic target worthy of further investigation. Thus, it is reasonable to consider that small molecule agonists of the noncanonical Wnt signaling pathway are potential new targets in GRN+ FTD. Since Wnt signaling is cell context and receptor dependent, gaining a full understanding of the other players in the pathway that may interact with FZD2 is crucial. This

work provides the impetus for further in depth exploration of Wnt signaling in FTD and suggests the potential use of Wnt agonists to assuage the neurodegenerative phenotype of GRN+ FTD. Human neural progenitor cells were infected, selected with puromycin, and http://www.selleckchem.com/products/sch-900776.html differentiated for 4 weeks. Microarray analysis was performed as reported previously (Konopka et al., 2009). See Supplemental Experimental Procedures for details. Postmortem expression data from FTD patients and controls was obtained from (Chen-Plotkin et al., 2008) (GSE13162:GSM329660-GSM329715). Network analysis was performed using previously published methods (Oldham et al., 2006, Oldham et al., 2008 and Winden

et al., 2009). Gene ontology (GO) analysis was performed using the DAVID functional annotation tool (http://david.abcc.ncifcrf.gov/) (Huang et al., 2009a and Huang et al., 2009b). See Supplemental Experimental Procedures for more details. Initially, the pLCIR plasmid was used containing CAG promoter, chosen because of its robust expression in neurons, driving shRNA against GRN. The control was a GFP hairpin used previously (Matsuda and Cepko, 2007). To knock down GRN in an inducible system, pTRIPZ vector was purchased from Open Biosystems (Huntsville, AL). Their scrambled pTRIPZ vector was used as a control, and their TRIPZ GRN hairpin

was used to knock down GRN. The sequence of the other GRN hairpin was obtained from (Zhang et al., 2007), and was cloned into TRIPZ using the PCR shagging protocol (http://katahdin.cshl.org:9331/RNAi/html/rnai.html). FZD2 knockdown was accomplished by purchasing Cytidine deaminase FZD2 hairpins in vector pLKO (Open Biosystems), and pLUIP was used to overexpress FZD2, containing a U6 promoter driving expression of FZD2 with PuroR driven by an IRES. More detailed material on plasmids and sequences can be found in Supplemental Experimental Procedures. Human neural progenitor cells (NHNPs) were generated from a 17-week gestation aborted female fetus. Tissue was homogenized, plated, and cultured as previously described (Svendsen et al., 1998 and Wexler et al., 2008), and further elaborated in the Supplemental Experimental Procedures.