Back to Search
Start Over
Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling.
- Source :
-
Neuron [Neuron] 2011 Sep 22; Vol. 71 (6), pp. 1030-42. Date of Electronic Publication: 2011 Sep 21. - Publication Year :
- 2011
-
Abstract
- Progranulin (GRN) mutations cause frontotemporal dementia (FTD), but GRN's function in the CNS remains largely unknown. To identify the pathways downstream of GRN, we used weighted gene coexpression network analysis (WGCNA) to develop a systems-level view of transcriptional alterations in a human neural progenitor model of GRN-deficiency. This highlighted key pathways such as apoptosis and ubiquitination in GRN deficient human neurons, while revealing an unexpected major role for the Wnt signaling pathway, which was confirmed by analysis of gene expression data from postmortem FTD brain. Furthermore, we observed that the Wnt receptor Fzd2 was one of only a few genes upregulated at 6 weeks in a GRN knockout mouse, and that FZD2 reduction caused increased apoptosis, while its upregulation promoted neuronal survival in vitro. Together, these in vitro and in vivo data point to an adaptive role for altered Wnt signaling in GRN deficiency-mediated FTD, representing a potential therapeutic target.<br /> (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cell Death
Cell Differentiation
Cells, Cultured
Frizzled Receptors genetics
Frizzled Receptors metabolism
Gene Expression Regulation
Gene Regulatory Networks
Humans
Intercellular Signaling Peptides and Proteins genetics
Mice
Microarray Analysis
Neural Stem Cells physiology
Neurons physiology
Progranulins
Receptors, G-Protein-Coupled genetics
Receptors, G-Protein-Coupled metabolism
Wnt Proteins genetics
Genome
Genomics methods
Intercellular Signaling Peptides and Proteins deficiency
Signal Transduction physiology
Wnt Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4199
- Volume :
- 71
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Neuron
- Publication Type :
- Academic Journal
- Accession number :
- 21943601
- Full Text :
- https://doi.org/10.1016/j.neuron.2011.07.021