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

Eric M. Wexler, Ezra Rosen, Daning Lu, Gregory E. Osborn, Elizabeth Martin, Helen E Raybould, Daniel H. Geschwind

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberra65
JournalScience Signaling
Volume4
Issue number193
DOIs
StatePublished - Oct 4 2011

Fingerprint

Gene Regulatory Networks
Genes
Wnt Signaling Pathway
Genome
Gene expression
Neurodegenerative diseases
Frontotemporal Dementia
Gene Expression
Neurodegenerative Diseases
Alzheimer Disease
Wnt Proteins
Waveform analysis
Catenins
Information Services
Independent component analysis
Cell death
Microarray Analysis
Microarrays
Brain
Cell Death

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways. / Wexler, Eric M.; Rosen, Ezra; Lu, Daning; Osborn, Gregory E.; Martin, Elizabeth; Raybould, Helen E; Geschwind, Daniel H.

In: Science Signaling, Vol. 4, No. 193, ra65, 04.10.2011.

Research output: Contribution to journalArticle

Wexler, Eric M. ; Rosen, Ezra ; Lu, Daning ; Osborn, Gregory E. ; Martin, Elizabeth ; Raybould, Helen E ; Geschwind, Daniel H. / Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways. In: Science Signaling. 2011 ; Vol. 4, No. 193.
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