title: Selective cortical layering abnormalities and behavioral deficits in cortex-specific Pax6 knock-out mice.
abstract: 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 Pax6(fl/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.
authors: Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors: Tran Cong
authors: TC
authors: Tuoc
authors: Konstantin
authors: K
authors: Radyushkin
authors: Anton B
authors: AB
authors: Tonchev
authors: Maria Carmen
authors: MC
authors: Piñon
authors: Ruth
authors: R
authors: Ashery-Padan
authors: Zoltán
authors: Z
authors: Molnár
authors: Michail S
authors: MS
authors: Davidoff
authors: Anastassia
authors: A
authors: Stoykova
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology; D001973:Bromodeoxyuridine / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000196:embryology / Q000254:growth & development / Q000473:pathology*; D003214:Conditioning, Classical / Q000502:physiology; D000013:Congenital Abnormalities / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005136:Eye Proteins; D005239:Fear / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D007211:Indoles; D019394:Ki-67 Antigen / Q000378:metabolism; D008569:Memory Disorders / Q000235:genetics; D001523:Mental Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D017288:Pain Threshold / Q000502:physiology; D051761:Paired Box Transcription Factors / Q000172:deficiency*; D011597:Psychomotor Performance / Q000502:physiology; D011930:Reaction Time / Q000235:genetics; D000091042:Reelin Protein; D012097:Repressor Proteins; D012697:Serine Endopeptidases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D001973:Bromodeoxyuridine; D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D007211:Indoles; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D000091042:Reelin Protein; D012097:Repressor Proteins; D012697:Serine Endopeptidases; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C000605730:PAX6 protein, human; C000605732:Pax6 protein, mouse; C007293:DAPI