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The Journal of Neuroscience, July 1, 2009, 29(26):8335-8349; doi:10.1523/JNEUROSCI.5669-08.2009
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Development/Plasticity/Repair
Selective Cortical Layering Abnormalities and Behavioral Deficits in Cortex-Specific Pax6 Knock-Out Mice
Tran Cong Tuoc,1,2 * Konstantin Radyushkin,1 * Anton B. Tonchev,3 Maria Carmen Piñon,4 Ruth Ashery-Padan,5 Zoltán Molnár,4 Michail S. Davidoff,6 andAnastassia Stoykova1,2 1Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany, 2Center of Molecular Physiology of the Brain, Deutsche Forschungsgemeinschaft, 37073 Göttingen, Germany, 3Laboratory of Cell Biology, Faculty of Pharmacy, Medical University, 9002 Varna, Bulgaria, 4Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom, 5Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel, and 6Department of Anatomy, University Medical Center Hamburg–Eppendorf, University of Hamburg, 20246 Hamburg, Germany
Correspondence should be addressed to Anastassia Stoykova, Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany. Email: astoyko{at}gwdg.de
The transcription factor Pax6 has been implicated in neocortical neurogenesis in vertebrates, including humans. Analyses of the role of Pax6 in layer formation and cognitive abilities have been hampered by perinatal lethality of Pax6 mutants. Here, we generated viable mutants exhibiting timed, restricted inactivation of Pax6 during early and late cortical neurogenesis using Emx1-Cre and hGFAP-Cre lines, respectively. The disruption of Pax6 at the onset of neurogenesis using Emx1-Cre line resulted in premature cell cycle exit of early progenitors, increase of early born neuronal subsets located in the marginal zone and lower layers, and a nearly complete absence of upper layer neurons, especially in the rostral cortex. Furthermore, progenitors, which accumulated in the enlarged germinal neuroepithelium at the pallial/subpallial border in the Pax6 mutants, produced an excess of oligodendrocytes. The inactivation of Pax6 after generation of the lower neuronal layers using hGFAP-Cre line did not affect specification or numbers of late-born neurons, indicating that the severe reduction of upper layer neurons in Pax6 deficiency is mostly attributable to a depletion of the progenitor pool, available for late neurogenesis. We further show that Pax6fl/fl;Emx1-Cre mutants exhibited deficiencies in sensorimotor information integration, and both hippocampus-dependent short-term and neocortex-dependent long-term memory recall. Because a majority of the morphological and behavior disabilities of the Pax6 mutant mice parallel abnormalities reported for aniridia patients, a condition caused by PAX6 haploinsufficiency, the Pax6 conditional mutant mice generated here represent a valuable genetic tool to understand how the developmental cortical disruption can lead to a human behavior abnormality.
Received Nov. 27, 2008; revised April 25, 2009; accepted May 18, 2009.
Correspondence should be addressed to Anastassia Stoykova, Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany. Email: astoyko{at}gwdg.de
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J. Neurosci. 2009 29: i.[Full Text]
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