Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways.

TitleGenome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways.
Publication TypeJournal Article
Year of Publication2011
AuthorsWexler, EM, Rosen E, Lu D, Osborn GE, Martin E, Raybould H, Geschwind DH
JournalScience signaling
Volume4
Issue193
Paginationra65
Date Published2011 Oct 4
ISSN1937-9145
KeywordsAlzheimer Disease, Cells, Cultured, Frontotemporal Dementia, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Humans, Intercellular Signaling Peptides and Proteins, Nerve Tissue Proteins, Oligonucleotide Array Sequence Analysis, Presenilin-1, Transcription, Genetic, Wnt Signaling Pathway, Wnt1 Protein
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.

DOI10.1038/nn.3115
Alternate JournalSci Signal