Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation.
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.
Schubert
Markus
M
Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Brazil
Derek P
DP
Burks
Deborah J
DJ
Kushner
Jake A
JA
Ye
Jing
J
Flint
Carrie L
CL
Farhang-Fallah
Janet
J
Dikkes
Pieter
P
Warot
Xavier M
XM
Rio
Carlos
C
Corfas
Gabriel
G
White
Morris F
MF
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D002452:Cell Count; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003433:Crosses, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006579:Heterozygote; D020287:In Situ Nick-End Labeling; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009929:Organ Size / Q000235:genetics; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D016875:tau Proteins; D017526:Receptor, IGF Type 1