Expression of Gtf2ird1, the Williams syndrome-associated gene, during mouse development

doi:10.1016/j.modgep.2006.11.008

Gene Expression Patterns

Volume 7, Issue 4, February 2007, Pages 396-404

https://doi.org/10.1016/j.modgep.2006.11.008 Get rights and content

Abstract

The gene GTF2IRD1 is localized within the critical region on chromosome 7 that is deleted in Williams syndrome patients. Genotype–phenotype comparisons of patients carrying variable deletions within this region have implicated GTF2IRD1 and a closely related homolog, GTF2I, as prime candidates for the causation of the principal symptoms of Williams syndrome. We have generated mice with an nls-LacZ knockin mutation of the Gtf2ird1 allele to study its functional role and examine its expression profile. In adults, expression is most prominent in neurons of the central and peripheral nervous system, the retina of the eye, the olfactory epithelium, the spiral ganglion of the cochlea, brown fat adipocytes and to a lesser degree myocytes of the heart and smooth muscle. During development, a dynamic pattern of expression is found predominantly in musculoskeletal tissues, the pituitary, craniofacial tissues, the eyes and tooth buds. Expression of Gtf2ird1 in these tissues correlates with the manifestation of some of the clinical features of Williams syndrome.

Section snippets

Gtf2ird1 and Williams syndrome clinical features

GTF2IRD1, GTF2I and GTF2IRD2 are members of a gene family that are located on chromosome 7q11.23 (Hinsley et al., 2004, Bayarsaihan et al., 2002). GTF2IRD1 and GTF2I are adjacent and GTF2IRD2 is separated from the GTF2I gene by the NCF1 gene. They all share considerable homology within a repeated domain, which confers sequence-specific DNA binding properties (Polly et al., 2003, Roy, 2001, Vullhorst and Buonanno, 2003, Vullhorst and Buonanno, 2005). The high homology and tight linkage suggest

Generation of Gtf2ird1^tm2(LacZ)Hrd mice

The mutant reporter allele was produced by targeted homologous recombination in 129 embryonic stem cells. Exon 2 of the Gtf2ird1 gene was replaced with a LacZ cDNA fused to a nuclear localisation signal (Kalderon et al., 1984). A pgkNEO cassette flanked by LoxP sites was inserted downstream to select for ES cell integrants. This cassette was removed after germ line transmission was established by inter-breeding with C57BL/6 mice that carry the CMV-Cre transgene (Schwenk et al., 1995). The

Acknowledgements

We thank Patrick Tam for critical review of the manuscript, Dr. Christine Biben for supplying the C57BL/6-CMV-Cre mice, Kata Popovic for help with genotyping, Minru Xiou for assistance with histology and Shahragim Tajbakhsh for supplying the nuclear localized LacZ cDNA cassette.

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Anxious, hypoactive phenotype combined with motor deficits in Gtf2ird1 null mouse model relevant to Williams syndrome
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Appendices include two tables with data from CatWalk gait analysis and a picture of limb grasping in hom animal on inversion. During mouse development, Gtf2ird1 displays a dynamic pattern of expression and is found predominantly in musculoskeletal tissues, the pituitary, craniofacial tissues, the eyes and tooth buds [49]. This pattern of expression is compatible with the phenotypes detected in our mouse model.
Williams–Beuren syndrome (WBS) is a rare genetic disorder caused by a hemizygous deletion of around 28 genes on the long arm of chromosome 7 (7q11.23), characterized by a unique spectrum of behavioral impairments, including mental retardation, deficits in visuospatial constructive cognition, hypersociability, anxiety and simple phobias. Physical characteristics include dysmorphic faces, short stature, oculomotor deficits, gross and fine coordination impairments, diminished control of balance and mild extrapyramidal signs as well as gait abnormalities resembling gait hypokinesia. Genes near the distal deletion breakpoint appear to contribute most to the WBS cognitive and behavioral profile and include the GTF family of transcription factors: GTF2I, GTF2IRD1, GTF2IRD2. We have previously shown that heterozygous deletions of GTF2IRD1 in humans and homozygous deletion in mice contributes to craniofacial abnormalities. Here we show an important role of this gene in motor coordination and anxiety ascertained from extensive behavioral mouse phenotyping. Gtf2ird1 null mice showed lower body weight, decreased spontaneous and circadian locomotor activity, diminished motor coordination and strength, gait abnormalities, increased anxiety and an elevated endocrinological response to stress. Gtf2ird1 heterozygous mice displayed lower body weight and decreased circadian activity, but only minor motor coordination and anxiety-related behavioral dysfunctions. Our study strongly supports a role for GTF2IRD1 in the motoric and anxiety-related abnormalities seen in Williams–Beuren syndrome, and suggests basal ganglia and potentially cerebellar abnormalities in Gtf2ird1 mice.
Mutation of Gtf2ird1 from the Williams-Beuren syndrome critical region results in facial dysplasia, motor dysfunction, and altered vocalisations
2012, Neurobiology of Disease
Citation Excerpt :
Post-hoc tests revealed both male (p < 0.01) and female (p < 0.01) homozygous Gtf2ird1tm1Hrd mice had decreased temperature compared to wild type controls. Since Gtf2ird1 is expressed from early embryogenesis onwards in a broad range of tissues including the developing brain (Palmer et al., 2007), it is possible that alterations in vocalisations may result from developmental abnormalities that are apparent at earlier time points. Maternal separation is a common paradigm used to elicit vocalisations from rodent pups, and would be directly comparable to vocalisation rates in adulthood.
Insufficiency of the transcriptional regulator GTF2IRD1 has become a strong potential explanation for some of the major characteristic features of the neurodevelopmental disorder Williams–Beuren syndrome (WBS). Genotype/phenotype correlations in humans indicate that the hemizygous loss of the GTF2IRD1 gene and an adjacent paralogue, GTF2I, play crucial roles in the neurocognitive and craniofacial aspects of the disease. In order to explore this genetic relationship in greater detail, we have generated a targeted Gtf2ird1 mutation in mice that blocks normal GTF2IRD1 protein production. Detailed analyses of homozygous null Gtf2ird1 mice have revealed a series of phenotypes that share some intriguing parallels with WBS. These include reduced body weight, a facial deformity resulting from localised epidermal hyperplasia, a motor coordination deficit, alterations in exploratory activity and, in response to specific stress-inducing stimuli; a novel audible vocalisation and increased serum corticosterone. Analysis of Gtf2ird1 expression patterns in the brain using a knock-in LacZ reporter and c-fos activity mapping illustrates the regions where these neurological abnormalities may originate. These data provide new mechanistic insight into the clinical genetic findings in WBS patients and indicate that insufficiency of GTF2IRD1 protein contributes to abnormalities of facial development, motor function and specific behavioural disorders that accompany this disease.
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This study looks at idiom comprehension by French-speaking people with Williams’ syndrome (WS) and metapragmatic knowledge is examined. Idiomatic expressions are a nonliteral form of language where there is a considerable difference between what is said (literal interpretation) and what is meant (idiomatic interpretation). WS is characterized by a relatively preserved formal language, social interest and poor conversational skills. Using this framework, the present study aims to explore the comprehension of idiomatic expressions by 20 participants with WS. Participants performed a story completion task (comprehension task), and a task of metapragmatic knowledge to justify their chosen answers. WS performances were compared to typically developing children with the same verbal mental age. The main results can be summarized as follows: (1) people with WS have difficulties to understand idioms; (2) WS group seems to perform partly as typically developing children for the acquisition of metapragmatic knowledge of linguistic convention: there is a progressive increase in metapragmatic knowledge of linguistic convention as age increased. Our results indicate a delay of acquisition in idiom comprehension in Williams’ syndrome.
Negative autoregulation of GTF2IRD1 in Williams-Beuren syndrome via a novel DNA binding mechanism
2010, Journal of Biological Chemistry
Citation Excerpt :
Because levels of transcript in KO mice are approximately double wild-type levels, we estimate that the truncated peptide is present at 6% of normal GTF2IRD1 protein levels. The phenotypic consequences of this mutation appear to be very similar to another KO line, in which exons 2–5 are deleted (22), and the Gtf2ird1tm2(LacZ)Hrd mutant line, in which LacZ has been inserted into exon 2 (20). Homozygous null mice from these lines do not have major developmental abnormalities, but show defects in brain function and behavioral alterations (22).5
The GTF2IRD1 gene is of principal interest to the study of Williams-Beuren syndrome (WBS). This neurodevelopmental disorder results from the hemizygous deletion of a region of chromosome 7q11.23 containing 28 genes including GTF2IRD1. WBS is thought to be caused by haploinsufficiency of certain dosage-sensitive genes within the deleted region, and the feature of supravalvular aortic stenosis (SVAS) has been attributed to reduced elastin caused by deletion of ELN. Human genetic mapping data have implicated two related genes GTF2IRD1 and GTF2I in the cause of some the key features of WBS, including craniofacial dysmorphology, hypersociability, and visuospatial deficits. Mice with mutations of the Gtf2ird1 allele show evidence of craniofacial abnormalities and behavioral changes. Here we show the existence of a negative autoregulatory mechanism that controls the level of GTF2IRD1 transcription via direct binding of the GTF2IRD1 protein to a highly conserved region of the GTF2IRD1 promoter containing an array of three binding sites. The affinity for this protein-DNA interaction is critically dependent upon multiple interactions between separate domains of the protein and at least two of the DNA binding sites. This autoregulatory mechanism leads to dosage compensation of GTF2IRD1 transcription in WBS patients. The GTF2IRD1 promoter represents the first established in vivo gene target of the GTF2IRD1 protein, and we use it to model its DNA interaction capabilities.
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Cholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer's disease (AD) and results are contradictory.
We performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.
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Expression of Gtf2ird1, the Williams syndrome-associated gene, during mouse development

Abstract

Section snippets

Gtf2ird1 and Williams syndrome clinical features

Generation of Gtf2ird1tm2(LacZ)Hrd mice

Acknowledgements

Genomics

Gene Exp. Patterns

Cell

Genomics

Genet. Med.

Dev. Biol.

Cell

J. Biol. Chem.

Brain Res. Bull.

Gene

Brain Res. Bull.

J. Biol. Chem.

J. Biol. Chem.

Isolation and characterization of BEN, a member of the TFII-I family of DNA-binding proteins containing distinct helix–loop–helix domains

Proc. Natl. Acad. Sci. USA

Molecular dissection of DNA sequences and factors involved in slow muscle-specific transcription

Mol. Cell. Biol.

Generation of Gtf2ird1^tm2(LacZ)Hrd mice