Phenotypic Analysis of A GTF2IRD1
Mouse Model of
Williams-Beuren Syndrome
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1
University of Toronto, Institute of Medical Science, United States
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2
University of Toronto, Department of Molecular Genetics, Canada
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3
University of Toronto, Department of Medicine, Canada
Williams-Beuren syndrome (WBS) is a complex disorder, caused by the hemizygous deletion of 26 genes on chromosome 7q11.23. WBS is characterized by a unique behavioral and cognitive profile, in addition to numerous physical symptoms, but although haploinsufficiency for the elastin gene has been shown to be responsible for the cardiovascular disease, no other gene has been unequivocally linked to this disorder. The common WBS deletion spans 1.55 million base pairs of DNA, and recent research has narrowed the region contributing to the major phenotypes to the telomeric portion, through the identification of individuals with smaller deletions.
We have generated a mouse model of one of the General Transcription Factor 2I (GTF2I) genes implicated in WBS and demonstrated neurological features similar to some of those seen in WBS. Mice with heterozygous or homozygous disruption of Gtf2ird1 exhibit decreased fear and aggression and increased social behaviors, reminiscent of the hypersociability and diminished fear of strangers that are hallmarks of Williams-Beuren syndrome. In addition, we identified amygdala-based learning difficulties, although hippocampal-based learning remained intact as evidenced by performance in the Morris water maze that was comparable to wild-type littermates.
The interaction between the orbitofrontal cortex (OFC) and the amygdala is thought be crucial for making appropriate social judgments. Lesions of the OFC are associated with social disinhibition, and disturbance of the functional interaction between the OFC and amygdala in subjects with WBS is thought to be contributing to social disinhibition, reduced reactivity to social cues and an increased tendency to approach strangers. We assessed brain activity in the amygdala and frontal cortex in our mouse model, through the analysis of expression of the immediate-early transcription factor gene, c-Fos, which is activated transiently and rapidly in response to a wide variety of cellular stimuli. In this case we used the open field test as a fear stimulus, since the Gtf2ird1-/- mice showed marked differences in their level of anxiety in this test, when compared to wild-type mice. We analyzed both baseline c-Fos expression, where tissue was taken from animals in their home cage, and expression of c-Fos in response to fear/stress, where tissue was taken 30 minutes after exposure to the open field. We assessed expression of both mRNA and protein using quantitative real-time PCR analysis of brain regions and immunostaining of whole brain sections. We found that baseline c-Fos mRNA expression was equivalent in the Gtf2ird1-/- and wild- type mice, but upon exposure to the open field, a 60% reduction in the expression of c-Fos was observed in the frontal cortex of Gtf2ird1-/- mice relative to wild-type mice. These results were confirmed by protein immunostaining, where we observed a decrease in c-Fos immunoreactivity in the medial prefrontal cortex, including the prelimbic and infralimbic cortex, and the cingulate cortex. These alterations in c-Fos protein correlate well with the changes in mRNA expression and suggest that there are significant differences in activation of the prefrontal cortex in response to fear/stress in our mouse model compared to wild type animals, which may correlate with the regionally reduced activity seen in subjects with WBS.
Conference:
12th International Professional Conference on Williams Syndrome, Garden Grove,CA, United States, 13 Jul - 14 Jul, 2008.
Presentation Type:
Oral Presentation
Topic:
SESSION 2: Animal Models of Williams Syndrome
Citation:
Young
EJ,
O'Leary
J,
Tam
E and
Osborne
LR
(2009). Phenotypic Analysis of A GTF2IRD1
Mouse Model of
Williams-Beuren Syndrome.
Conference Abstract:
12th International Professional Conference on Williams Syndrome.
doi: 10.3389/conf.neuro.09.2009.07.006
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Received:
29 Apr 2009;
Published Online:
29 Apr 2009.
*
Correspondence:
E. J Young, University of Toronto, Institute of Medical Science, Toronto, United States, Toronto.lucy.osborne@utoronto.ca