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Expression of constitutively active FoxO3 in murine forebrain leads to a loss of neural progenitors
Author(s) -
SchmidtStrassburger Uta,
Schips Tobias G.,
Maier Harald J.,
Kloiber Katharina,
Mannella Francesca,
Braunstein Kerstin E.,
Holzmann Karlheinz,
Ushmorov Alexey,
Liebau Stefan,
Boeckers Tobias M.,
Wirth Thomas
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-208587
Subject(s) - neurogenesis , forebrain , subventricular zone , progenitor cell , biology , neural stem cell , microbiology and biotechnology , transgene , genetically modified mouse , progenitor , endocrinology , stem cell , genetics , central nervous system , gene
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.—Schmidt‐Strassburger, U., Schips, T. G., Maier, H. J., Kloiber, K., Mannella, F., Braunstein, K. E., Holzmann, K., Ushmorov, A., Liebau, S., Boeckers, T. M., Wirth, T. Expression of constitutively active FoxO3 in murine forebrain leads to a loss of neural progenitors. FASEB J. 26, 4990–5001 (2012). www.fasebj.org