Research ArticleNeuroscience

Genome-Wide Analysis of a Wnt1-Regulated Transcriptional Network Implicates Neurodegenerative Pathways

Science Signaling  04 Oct 2011:
Vol. 4, Issue 193, pp. ra65
DOI: 10.1126/scisignal.2002282

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Networking Wnt into Neurodegeneration

Wnt signaling, which is crucial to brain development, has also been implicated in neurodegenerative diseases. Noting that Wnt activates various signaling pathways, which may involve numerous effectors, Wexler et al. performed a genome-wide analysis of the response of cultured human neural progenitor cells to Wnt1. Over the course of 3 days, they observed an oscillatory pattern of changes in the abundance of gene transcripts, including genes associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia (FTD). Having used computational analyses to identify a potential link between Wnt signaling and progranulin, deficiency of which is associated with FTD, the authors defined a reciprocal relationship between the two. Wnt1 signaling led to a decrease in progranulin abundance, whereas progranulin knockdown increased Wnt1 mRNA. Moreover, Wnt expression was increased in cortical tissue from people with an inherited form of FTD associated with haploinsufficiency of the gene encoding progranulin. Thus, their data are consistent with a role for Wnt signaling in FTD and possibly other neurodegenerative diseases.