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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

Authors for correspondence (e-mail: zhaocj{at}seu.edu.cn or samuelp{at}itsa.ucsf.edu)

Accepted 15 April 2005

Wnt signaling regulates hippocampal development but little is known about the functions of specific Wnt receptors in this structure. Frizzled 9 is selectively expressed in the hippocampus and is one of about 20 genes typically deleted in Williams syndrome. Since Williams syndrome is associated with severe visuospatial processing defects, we generated a targeted null allele for frizzled 9 to examine its role in hippocampal development. Frizzled 9-null mice had generally normal gross anatomical hippocampal organization but showed large increases in apoptotic cell death in the developing dentate gyrus. This increase in programmed cell death commenced with the onset of dentate gyrus development and persisted into the first postnatal week of life. There was also a perhaps compensatory increase in the number of dividing precursors in the dentate gyrus, which may have been a compensatory response to the increased cell death. These changes in the mutants resulted in a moderate decrease in the number of adult dentate granule cells in null mice and an increase in the number of hilar mossy cells. Heterozygous mice (the same frizzled 9 genotype as Williams syndrome patients) were intermediate between wild type and null mice for all developmental neuronanatomic defects. All mice with a mutant allele had diminished seizure thresholds, and frizzled 9 null mice had severe deficits on tests of visuospatial learning/memory. We conclude that frizzled 9 is a critical determinant of hippocampal development and is very likely to be a contributing factor to the neurodevelopmental and behavioral phenotype of patients with Williams syndrome.

Key words: Wnt, Dentate gyrus, Epilepsy, Mossy cell, Apoptosis

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