title: Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways.
abstract: Wnt proteins are critical to mammalian brain development and function. The canonical Wnt signaling pathway involves the stabilization and nuclear translocation of β-catenin; however, Wnt also signals through alternative, noncanonical pathways. To gain a systems-level, genome-wide view of Wnt signaling, we analyzed Wnt1-stimulated changes in gene expression by transcriptional microarray analysis in cultured human neural progenitor (hNP) cells at multiple time points over a 72-hour time course. We observed a widespread oscillatory-like pattern of changes in gene expression, involving components of both the canonical and the noncanonical Wnt signaling pathways. A higher-order, systems-level analysis that combined independent component analysis, waveform analysis, and mutual information-based network construction revealed effects on pathways related to cell death and neurodegenerative disease. Wnt effectors were tightly clustered with presenilin1 (PSEN1) and granulin (GRN), which cause dominantly inherited forms of Alzheimer's disease and frontotemporal dementia (FTD), respectively. We further explored a potential link between Wnt1 and GRN and found that Wnt1 decreased GRN expression by hNPs. Conversely, GRN knockdown increased WNT1 expression, demonstrating that Wnt and GRN reciprocally regulate each other. Finally, we provided in vivo validation of the in vitro findings by analyzing gene expression data from individuals with FTD. These unbiased and genome-wide analyses provide evidence for a connection between Wnt signaling and the transcriptional regulation of neurodegenerative disease genes.
authors.affiliation: Department of Psychiatry, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90024, USA. ewexler@ucla.edu
authors.forename: Eric M
authors.initials: EM
authors.lastname: Wexler
authors.forename: Ezra
authors.initials: E
authors.lastname: Rosen
authors.forename: Daning
authors.initials: D
authors.lastname: Lu
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Osborn
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Martin
authors.forename: Helen
authors.initials: H
authors.lastname: Raybould
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D053764:Presenilin-1 / Q000096:biosynthesis / Q000235:genetics; D000077153:Progranulins; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D000077153:Progranulins; C495247:WNT1 protein, human; D051155:Wnt1 Protein