Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling.
Neuron
; 71(6): 1030-42, 2011 Sep 22.
Article
en En
| MEDLINE
| ID: mdl-21943601
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Genoma
/
Genómica
/
Péptidos y Proteínas de Señalización Intercelular
/
Proteínas Wnt
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Neuron
Asunto de la revista:
NEUROLOGIA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos