TY - JOUR
T1 - Functional Genomic Analyses Identify Pathways Dysregulated by Progranulin Deficiency, Implicating Wnt Signaling
AU - Rosen, Ezra Y.
AU - Wexler, Eric M.
AU - Versano, Revital
AU - Coppola, Giovanni
AU - Gao, Fuying
AU - Winden, Kellen D.
AU - Oldham, Michael C.
AU - Martens, Lauren Herl
AU - Zhou, Ping
AU - Farese, Robert V.
AU - Geschwind, Daniel H.
N1 - Funding Information:
This work was supported by the Consortium for Frontotemporal Dementia (CFR). This work was supported by NIA 5R01AG026938 (D.H.G.), by NIH/NINDS Neurobehavioral Genetics Training Grant 5T32NS048004-05 (E.Y.R.), the John Douglas French Alzheimer's Foundation and NIMH K08MH74362 (E.M.W.), and by NIH AG034793 (L.H.M.). We are also grateful to Jeremy Miller for critical reading of this manuscript and we would like to thank Lauren Kawaguchi for her expertise as laboratory manager.
PY - 2011/9/22
Y1 - 2011/9/22
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/80053098817
U2 - 10.1016/j.neuron.2011.07.021
DO - 10.1016/j.neuron.2011.07.021
M3 - Article
C2 - 21943601
AN - SCOPUS:80053098817
SN - 0896-6273
VL - 71
SP - 1030
EP - 1042
JO - Neuron
JF - Neuron
IS - 6
ER -