Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation
Open accessAbstract
Insulin resistance and diabetes might promote neurodegenerative disease, but a molecular link between these disorders is unknown. Many factors are responsible for brain growth, patterning, and survival, including the insulin-insulin-like growth factor (IGF)-signaling cascades that are mediated by tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. Irs2 signaling mediates peripheral insulin action and pancreatic beta-cell function, and its failure causes diabetes in mice. In this study, we reveal two important roles for Irs2 signaling in the mouse brain. First, disruption of the Irs2 gene reduced neuronal proliferation during development by 50%, which dissociated brain growth from Irs1-dependent body growth. Second, neurofibrillary tangles containing phosphorylated tau accumulated in the hippocampus of old Irs2 knock-out mice, suggesting that Irs2 signaling is neuroprotective. Thus, dysregulation of the Irs2 branch of the insulin-Igf-signaling cascade reveals a molecular link between diabetes and neurodegenerative disease.
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This astrocyte subcluster was enriched for genes involved in extracellular matrix organization, metabolic support, and inflammatory modulation.
“This subcluster was enriched for genes involved in extracellular matrix organization [102, 135, 136], metabolic support [135, 137], and inflammatory modulation [138–141].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [137]
The Introduction mentions extracellular matrix proteins as factors in brain development, and the brain-growth results report GFAP staining of astrocytes. Neither passage identifies an astrocyte subcluster or reports enrichment of genes for extracellular matrix organization or metabolic support. Searches for those terms found no passage addressing the attributed finding; the inflammatory-modulation clause has separate citations in the citing sentence. (LLM, conf=0.77)
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- Authors
- Schubert, M., Brazil, D. P., Burks, D. J., Kushner, J. A., Ye, J., Flint, C. L., Farhang-Fallah, J., Dikkes, P., Warot, X. M., Rio, C., Corfas, G., & White, M. F.
- Affiliations
- Joslin Diabetes Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-08-06
- Volume
- 23
- Issue
- 18
- Pages
- 7084-7092
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740672
- OpenAlex
- W1508589930
- Cited by
- 488
- References
- 6
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 10 · 2023: 23 · 2022: 25 · 2021: 19 · 2020: 25 · 2019: 20 · 2018: 16 · 2017: 18 · 2016: 21 · 2015: 23 · 2014: 33 · 2013: 34 · 2012: 29
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK38712)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 43808, DK 38712, R01DK038712, R01DK043808)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- insulin receptor substrate 2, insulin signaling, IGF signaling, brain growth, neuronal proliferation, tau phosphorylation, neurofibrillary tangles, hippocampus, neurodegeneration, diabetes mellitus, insulin resistance, IRS-1, neuroprotection
- MeSH terms
- Age Factors, Animals, Body Weight, Brain, Cell Count, Cell Division, Cell Survival, Cells, Cultured, Cerebellum, Crosses, Genetic, Enzyme Inhibitors, Heterozygote, Neurons, Organ Size, Phosphoproteins, Phosphorylation, Signal Transduction, tau Proteins, Apoptosis, Receptor, IGF Type 1, Mice, Knockout, In Situ Nick-End Labeling, Intracellular Signaling Peptides and Proteins, Mice, Insulin Receptor Substrate Proteins
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