Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling.

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.

• Authors: Ezra Y Rosen, Eric M Wexler, Revital Versano, Giovanni Coppola, Fuying Gao, Kellen D Winden, Michael C Oldham, Lauren Herl Martens, Ping Zhou, Robert V Farese Jr, Daniel H Geschwind
• Journal: Neuron (Neuron) Vol. 71 Issue 6 Pg. 1030-42 (Sep 22 2011) ISSN: 1097-4199 [Electronic] United States
• PMID: 21943601 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• FZD2 protein, human
• Frizzled Receptors
• GRN protein, human
• Intercellular Signaling Peptides and Proteins
• Progranulins
• Receptors, G-Protein-Coupled
• Wnt Proteins

Topics

• Animals
• Cell Death
• Cell Differentiation
• Cells, Cultured
• Frizzled Receptors (genetics, metabolism)
• Gene Expression Regulation
• Gene Regulatory Networks
• Genome
• Genomics (methods)
• Humans
• Intercellular Signaling Peptides and Proteins (deficiency, genetics)
• Mice
• Microarray Analysis
• Neural Stem Cells (physiology)
• Neurons (physiology)
• Progranulins
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Signal Transduction (physiology)
• Wnt Proteins (genetics, metabolism)