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Expression of constitutively active FOXO3 in murine forebrain leads to a loss of neural progenitors

ABSTRACT: We have generated transgenic mice with tetracycline-regulated conditional expression of a constitutively active allele of FoxO3 under the control of the forebrain-specific CaMKIIa promoter. In adult animals, there was a reduction of brain weight by 30% and an almost complete loss of the dorsal dentate gyrus with normal cortical layering. Interestingly, the adult mice showed motor hyperactivity and a selective loss of long-term memory with normal spatial learning. We observed enhanced apoptosis starting from day E10.5. Performing microarray expression analyses and Q-PCR validation with E12.5 forebrain RNA, we observed an over-representation of thalamic markers and an under-representation of cortical markers in transgenic as compared to control animals. Immunohistochemical data show a loss of progenitors in the lateral ventricles. Up-regulation of Pik3ip1 as a target gene of FoxO3 could be responsible for the observed increase in apoptosis. The obtained forebrain expression signature is reminiscent of a Pax6 knockdown phenotype showing that expression of this FoxO3 allele during development affected neural progenitor survival and overall brain development. Conclusion: Neural progenitors are vulnerable to constitutively active FoxO3-induced apoptosis. We sought to determine the transcriptional differences in forebrains from E12.5 mice expressing a constitutively active alleleof FoxO3 under the control of the forebrain-specific CaMKIIa promoter. To this end two time-pregnant dams were sacrificed 12 days after the vaginal plug was detected, and the embryos were prepared. Visual staging of the embryos confirmed their age. Genotyping and luciferase measurements were performed in order to assess presence and acitivity of the transgenes.

ORGANISM(S): Mus musculus  

SUBMITTER: Uta Schmidt-Strassburger   Nina Ushmorova  Karlheinz Holzmann  Thomas Wirth 

PROVIDER: E-GEOD-21089 | ArrayExpress | 2012-09-13



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Expression of constitutively active FoxO3 in murine forebrain leads to a loss of neural progenitors.

Schmidt-Strassburger Uta U   Schips Tobias G TG   Maier Harald J HJ   Kloiber Katharina K   Mannella Francesca F   Braunstein Kerstin E KE   Holzmann Karlheinz K   Ushmorov Alexey A   Liebau Stefan S   Boeckers Tobias M TM   Wirth Thomas T  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20120830 12

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 co  ...[more]

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