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Sci. Signal., 4 October 2011
Vol. 4, Issue 193, p. ra65
[DOI: 10.1126/scisignal.2002282]

RESEARCH ARTICLES

Genome-Wide Analysis of a Wnt1-Regulated Transcriptional Network Implicates Neurodegenerative Pathways

Eric M. Wexler1,2*, Ezra Rosen1,2, Daning Lu1,2, Gregory E. Osborn1,2, Elizabeth Martin3, Helen Raybould3, and Daniel H. Geschwind1,2,4,5

1 Department of Psychiatry, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90024, USA.
2 Program in Neurobehavioral Genetics, The Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90024, USA.
3 Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine at University of California, Davis, Davis, CA 95616, USA.
4 Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90024, USA.
5 Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90024, USA.

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.

* To whom correspondence should be addressed. E-mail: ewexler{at}ucla.edu

Citation: E. M. Wexler, E. Rosen, D. Lu, G. E. Osborn, E. Martin, H. Raybould, D. H. Geschwind, Genome-Wide Analysis of a Wnt1-Regulated Transcriptional Network Implicates Neurodegenerative Pathways. Sci. Signal. 4, ra65 (2011).

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