Expression of constitutively active FoxO3 in murine forebrain leads to a loss of neural progenitors.
FASEB J, 2012/12;26(12):4990-5001.
Schmidt-Strassburger U[1], Schips TG, Maier HJ, Kloiber K, Mannella F, Braunstein KE, Holzmann K, Ushmorov A, Liebau S, Boeckers TM, Wirth T
Affiliations
PMID: 22935140DOI: 10.1096/fj.12-208587
Impact factor: 5.834
Abstract
Inactivation of FoxO proteins by phosphorylation is the result of a number of stimuli, including the insulin/IGF pathway. We were interested in the consequence of blunting this pathway by employing transgenic mice with tetracycline-controllable conditional expression of a constitutively active allele of FOXO3 under the control of the forebrain-specific CaMKIIα promoter. Although transgene-expressing mice were viable, brain weight was reduced by 30% in adult animals. Brains showed an isocortex compression with normal cortical layering, and a size reduction in regions known to depend on adult neurogenesis, i.e., the olfactory bulbs and the dentate gyrus. On postnatal activation of the transgene, adult neurogenesis was also severely affected. Investigating the molecular basis of this phenotype, we observed enhanced apoptosis starting from embryonic day E10.5 and a subsequent loss of progenitors in the ventricular/subventricular zones, but not in the isocortex or the striatum of adult mice. The enhanced apoptosis was accompanied by increased expression of PIK3IP1, which we identified as a direct transcriptional target of FOXO3. Transfection of Pik3ip1 into differentiating neural progenitors resulted in a significant reduction of viable cells. We therefore conclude that neural progenitors are particularly vulnerable to FOXO3-induced apoptosis, which is mediated by PIK3IP1, a negative PI3 kinase regulator.
MeSH terms
Animals; Apoptosis; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Carrier Proteins; Cells, Cultured; Cluster Analysis; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Profiling; Gene Expression Regulation, Developmental; Immunoblotting; Intracellular Signaling Peptides and Proteins; Lateral Ventricles; Membrane Proteins; Mice; Mice, Inbred Strains; Mice, Transgenic; Mutation; Neural Stem Cells; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Prosencephalon; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction; Time Factors
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