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Isolation and Culture of Neural Crest Cells from Embryonic Murine Neural Tube
Published on: June 2, 2012
Expression of constitutively active FoxO3 in murine forebrain leads to a loss of neural progenitors
Uta Schmidt-Strassburger1, Tobias G Schips, Harald J Maier
1Institute of Physiological Chemistry, Ulm University, Albert Einstein Allee 11, 89081 Ulm, Germany.
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.
Insights
Activating FOXO3 in the brain reduces brain weight and impairs neurogenesis by increasing apoptosis in neural progenitors, mediated by PIK3IP1.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Forkhead box O (FoxO) proteins are key regulators of cellular processes, including stress resistance, metabolism, and cell cycle arrest.
- Inactivation of FoxO proteins via phosphorylation is triggered by stimuli like the insulin/IGF pathway.
- The role of FoxO proteins in brain development and neurogenesis remains incompletely understood.
Purpose of the Study:
- To investigate the consequences of blunting the insulin/IGF pathway by conditionally overexpressing a constitutively active FOXO3 allele in the forebrain.
- To elucidate the molecular mechanisms underlying the observed brain phenotype, focusing on apoptosis and neurogenesis.
Main Methods:
- Generation of transgenic mice with tetracycline-controllable conditional expression of constitutively active FOXO3 in the forebrain.
- Analysis of brain morphology, weight, and specific brain regions (olfactory bulbs, dentate gyrus, isocortex, striatum).
- Investigation of apoptosis, progenitor cell populations, and gene expression (PIK3IP1) during embryonic and postnatal development.
Main Results:
- Transgenic mice exhibited a 30% reduction in brain weight and isocortex compression.
- Significant size reduction in olfactory bulbs and dentate gyrus, regions dependent on adult neurogenesis.
- Postnatal activation of the transgene severely affected adult neurogenesis.
- Enhanced apoptosis and loss of progenitors in ventricular/subventricular zones from embryonic day E10.5.
- Increased expression of PIK3IP1, a direct transcriptional target of FOXO3, correlated with enhanced apoptosis.
- Transfection of Pik3ip1 reduced viable neural progenitor cells.
Conclusions:
- Neural progenitors are particularly vulnerable to FOXO3-induced apoptosis.
- FOXO3-mediated apoptosis in neural progenitors is regulated by PIK3IP1, a negative regulator of the PI3 kinase pathway.
- Blunting the insulin/IGF pathway in the forebrain leads to severe neurodevelopmental defects due to enhanced progenitor cell apoptosis.
