Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice.
Increased glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders like Alzheimer's disease and diabetes, thus supporting therapeutic potential of GSK-3 inhibitors. However, sustained GSK-3 inhibition might induce tumorigenesis through beta-catenin-APC dysregulation. Besides, sustained in vivo inhibition by genetic means (constitutive knock-out mice) revealed unexpected embryonic lethality due to massive hepatocyte apoptosis. Here, we have generated transgenic mice with conditional (tetracycline system) expression of dominant-negative-GSK-3 as an alternative genetic approach to predict the outcome of chronic GSK-3 inhibition, either per se, or in combination with mouse models of disease. By choosing a postnatal neuron-specific promoter, here we specifically address the neurological consequences. Tet/DN-GSK-3 mice showed increased neuronal apoptosis and impaired motor coordination. Interestingly, DN-GSK-3 expression shut-down restored normal GSK-3 activity and re-established normal incidence of apoptosis and motor coordination. These results reveal the importance of intact GSK-3 activity for adult neuron viability and physiology and warn of potential neurological toxicity of GSK-3 pharmacological inhibition beyond physiological levels. Interestingly, the reversibility data also suggest that unwanted side effects are likely to revert if excessive GSK-3 inhibition is halted.
Gómez-Sintes
Raquel
R
Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, Spain.
Hernández
Félix
F
Bortolozzi
Analía
A
Artigas
Francesc
F
Avila
Jesús
J
Zaratin
Paola
P
Gotteland
Jean Pierre
JP
Lucas
José J
JJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D004318:Doxycycline / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D016548:Prosencephalon / Q000166:cytology* / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology
D038362:Glycogen Synthase Kinase 3; D004318:Doxycycline