Functional Genomic Analyses Identify Pathways Dysregulated by Progranulin Deficiency, Implicating Wnt Signaling
Open accessAbstract
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.
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Experimental validation of predictions from these networks showed that cross-species approaches can identify consistent, high-confidence perturbations in neurodegenerative disease.
“Experimental validation of predictions from these networks showed that this cross-species approach can identify consistent, high-confidence perturbations in neurodegenerative disease46,153.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [153]
Those studies identified transcriptomic changes shared across post-mortem human brain, human neural cell lines, and mouse brain.
“Both involved extensive bioinformatic analyses of expression data from in vitro neural progenitor models and identified transcriptomic changes shared across the post-mortem human brain, human neural cell lines and the mouse brain.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [153]
In FTD, two studies re-analysed published transcriptome data and discovered a role for WNT signalling in GRN-mediated FTD.
“In FTD, two studies re-analysed published transcriptome data139 to discover a role for WNT signalling in GRN-mediated FTD153,154.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [153]
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References 74 · Cited by 128
- Authors
- Rosen, E. Y., Wexler, E. M., Versano, R., Coppola, G., Gao, F., Winden, K. D., Oldham, M. C., Martens, L. H., Zhou, P., Farese, R. V., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- University of California, San Francisco (US)
- Corresponding author
- Geschwind, Daniel H.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 71
- Issue
- 6
- Pages
- 1030-1042
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3633414
- OpenAlex
- W2037457942
- Cited by
- 128
- References
- 74
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 7 · 2022: 6 · 2021: 12 · 2020: 5 · 2019: 10 · 2018: 11 · 2017: 7 · 2016: 12 · 2015: 8 · 2014: 17 · 2013: 13 · 2012: 12
- FWCI
- 8.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (F31AG034793, AG034793, R01AG026938)
- National Institute of Mental Health (K08MH074362, T32MH073526)
- National Institute of Neurological Disorders and Stroke (T32NS048004)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- progranulin, frontotemporal dementia, Wnt signaling, FZD2, neural progenitor cells, apoptosis, ubiquitination, transcriptional dysregulation, neuronal survival, therapeutic target
- MeSH terms
- Progranulins, Animals, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Humans, Neurons, Signal Transduction, Genome, Cell Death, Genomics, Intercellular Signaling Peptides and Proteins, Receptors, G-Protein-Coupled, Microarray Analysis, Wnt Proteins, Frizzled Receptors, Mice, Gene Regulatory Networks, Neural Stem Cells
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