title: Expression of constitutively active FoxO3 in murine forebrain leads to a loss of neural progenitors.
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.
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Schmidt-Strassburger
authors.forename: Tobias G
authors.initials: TG
authors.lastname: Schips
authors.forename: Harald J
authors.initials: HJ
authors.lastname: Maier
authors.forename: Katharina
authors.initials: K
authors.lastname: Kloiber
authors.forename: Francesca
authors.initials: F
authors.lastname: Mannella
authors.forename: Kerstin E
authors.initials: KE
authors.lastname: Braunstein
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Holzmann
authors.forename: Alexey
authors.initials: A
authors.lastname: Ushmorov
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016000:Cluster Analysis; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D020547:Lateral Ventricles / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016548:Prosencephalon / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C579635:Pik3ip1 protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2