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First published online June 1, 2005
doi: 10.1242/10.1242/dev.01871

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Hippocampal and visuospatial learning defects in mice with a deletion of frizzled 9, a gene in the Williams syndrome deletion interval

Chunjie Zhao^1,*,, Carmen Avilés¹, Regina A. Abel³, C. Robert Almli³, Patrick McQuillen² and Samuel J. Pleasure^1,

¹ Department of Neurology, Graduate Programs in Neuroscience, Developmental Biology and Biomedical Sciences, Room S-268, 513 Parnassus Avenue, University of California, San Francisco, CA 94143, USA
² Department of Pediatrics, University of California, San Francisco, CA 94143, USA
³ Departments of Neurology, Psychology, Developmental Neuropsychobiology Laboratory, Programs in Occupational Therapy, Neuroscience, Washington University Medical School, St Louis, MO 63108, USA

View larger version (31K): [in a new window]   Fig. 1. Targeting the frizzled 9 allele. (A) Targeting strategy to generate the frizzled 9 null allele. The location of the genotyping primers and Southern probe are shown. (B) Southern blot showing the targeted allele. (C) RT-PCR for frizzled 9 and LacZ in mutant mice.

View larger version (75K): [in a new window]   Fig. 2. Precursor proliferation in the brains of frizzled 9 mutants. (A) Phospho-Histone-H3 is a marker of M-Phase of the cell cycle. Shown are examples of staining from brains at E14.5, E18.5 and P8. (B) Semi-quantitative analysis of the numbers of M-Phase cells showing significant increases in the medial cortical wall of mutant mice at E14.5 and in the dentate gyrus of E18.5 mutants but not P8 or adults. (C) Similar analysis of the numbers of BrdU labeled nuclei after acute BrdU administration at E18.5. *P<0.05; **P<0.005.

View larger version (53K): [in a new window]   Fig. 3. Stereologic analysis of the adult hippocampus. (A) Prox1 antibody staining of the dentate showing that the overall organization of the dentate is intact in frizzled 9 mutants. (B) Heterozygous and null frizzled 9 mutants have small but statistically significant decreases in the number of dentate granule cells but normal numbers of pyramidal neurons. For each genotype six animals (three male and three female) were used for counting.

View larger version (87K): [in a new window]   Fig. 4. Increased apoptotic cell death in frizzled 9 mutants. (A) TUNEL staining at E12.5, E14.5, E18.5 and P8 mice. The dotted lines outline the forming dentate gyrus at E18.5 and the dentate granule cell layer at P8. At E12.5, note the numerous labeled cells at the exact midline where the choroid forms but very few cells in the cortical hem (CH) or ventricular zone dorsal to it. (B) Counting of individual labeled cells and clusters of cells expressed at % of wild type. *P<0.05; **P<0.005.

View larger version (101K): [in a new window]   Fig. 5. Increased numbers of hilar mossy cells. (A-F) Calretinin antibody staining shown at low power and high power for all three genotypes. Note the increased density of calretinin labeled cell bodies in the hilus. (G) Quantitation of mossy cell number shows that there is a substantial and significant increase in their numbers in both heterozygous and mutant mice. These cells were counted from the same section series as those used for stereologic analysis. *P<0.05.

View larger version (45K): [in a new window]   Fig. 6. Seizure latency is decreased in frizzled 9 mutants. (A) Time in seconds to first twitch and to tonic-clonic seizure are shown. The latency of +/– and –/– mice is about half for each endpoint. n=6 for each genotype with 3 females and 3 males of each genotype. *P<0.05. (B) GFAP immunostaining in adult frizzled 9 +/+, +/– and –/– mice. (C) Calbindin immunostaining in adult frizzled 9 +/+, +/– and –/– mice.

View larger version (10K): [in a new window]   Fig. 7. Measures of spatial memory performance of frizzled 9 mutant mice [+/+ (n=8), +/– (n=12), –/– (n=9)] tested in the Morris water maze (Morris, 1984) under the place/spatial testing condition. Presented are Probe Times in seconds (A) and Number of Annulus Crossings (B) measured during probe trials (i.e. memory trials). The frizzled 9 mutant (–/–) mice displayed significantly (*P<0.04) poorer spatial memory performance on both measures than the +/+ mice, and the +/– mice tended to be intermediate.

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