title: FoxG1 haploinsufficiency results in impaired neurogenesis in the postnatal hippocampus and contextual memory deficits.
abstract: FoxG1 (formerly BF-1) encodes a transcription factor that regulates neurogenesis in the embryonic telencephalon. The current study suggests that FoxG1 also regulates neurogenesis in the postnatal hippocampus. FoxG1 continues to be strongly expressed in areas of known postnatal neurogenesis, including the subventricular zone of the lateral ventricle and the dentate gyrus (DG) of the hippocampus. Remarkably, FoxG1+/- mice have a 60% decrease in the total number of hippocampal dentate granule cells that is related to a loss of DG neurogenesis. Comparison of acute and chronic BrdU labeling, and PSA-NCAM staining suggests that the stage at which this loss of neurogenesis occurs progresses with age. Juvenile mice FoxG1+/- primarily show failed apparent survival of postnatally born DG neurons, whereas adult FoxG1+/- mice also show impairment of proliferation and initial DG neuron differentiation. Consistent with this process predominantly affecting postnatal hippocampal neurogenesis, BrdU pulses at embryonic days 16, 17, and 18 labels a higher percentage of DG cells in 6-week-old FoxG1+/- mice than in littermate controls. In contrast to the marked effect of FoxG1 haploinsufficiency on postnatal hippocampal neurogenesis, postnatal neurogenesis of olfactory bulb interneurons is grossly unaffected. Behaviorally, FoxG1+/- mice show hyperlocomotion and impaired habituation in the open field, and a severe deficit in contextual fear conditioning that are suggestive of impaired hippocampal function. Although mechanistic connections between FoxG1 haploinsufficiency and either failed postnatal DG neurogenesis or the behavioral deficits remain to be elucidated, these results present a new model system for impaired postnatal neurogenesis in the DG of adult mice.
authors.affiliation: Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Lijian
authors.initials: L
authors.lastname: Shen
authors.forename: Hyung-Song
authors.initials: HS
authors.lastname: Nam
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.forename: Holly
authors.initials: H
authors.lastname: Moore
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000502:physiology; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D018891:Dentate Gyrus / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006624:Hippocampus / Q000002:abnormalities* / Q000254:growth & development* / Q000503:physiopathology; D006948:Hyperkinesis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D013234:Stem Cells / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; D009419:Nerve Tissue Proteins; D001973:Bromodeoxyuridine