title: 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.affiliation: Interdepartmental Program for Neuroscience, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ezra Y
authors.initials: EY
authors.lastname: Rosen
authors.forename: Eric M
authors.initials: EM
authors.lastname: Wexler
authors.forename: Revital
authors.initials: R
authors.lastname: Versano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Fuying
authors.initials: F
authors.lastname: Gao
authors.forename: Kellen D
authors.initials: KD
authors.lastname: Winden
authors.forename: Michael C
authors.initials: MC
authors.lastname: Oldham
authors.forename: Lauren Herl
authors.initials: LH
authors.lastname: Martens
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D002478:Cells, Cultured; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D016678:Genome; D023281:Genomics / Q000379:methods*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D046228:Microarray Analysis; D058953:Neural Stem Cells / Q000502:physiology; D009474:Neurons / Q000502:physiology; D000077153:Progranulins; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C489742:FZD2 protein, human; D051157:Frizzled Receptors; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins