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Essential role of the N-terminal region of TFII-I in viability and behavior.

Lucena J, Pezzi S, Aso E, Valero MC, Carreiro C, Dubus P, Sampaio A, Segura M, Barthelemy I, Zindel MY, Sousa N, Barbero JL, Maldonado R, Pérez-Jurado LA, Campuzano V - BMC Med. Genet. (2010)

Bottom Line: Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs.Our data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression of GTF2I is one of the main players.In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at the in vivo model.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetics Unit, de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

ABSTRACT

Background: GTF2I codes for a general intrinsic transcription factor and calcium channel regulator TFII-I, with high and ubiquitous expression, and a strong candidate for involvement in the morphological and neuro-developmental anomalies of the Williams-Beuren syndrome (WBS). WBS is a genetic disorder due to a recurring deletion of about 1,55-1,83 Mb containing 25-28 genes in chromosome band 7q11.23 including GTF2I. Completed homozygous loss of either the Gtf2i or Gtf2ird1 function in mice provided additional evidence for the involvement of both genes in the craniofacial and cognitive phenotype. Unfortunately nothing is now about the behavioral characterization of heterozygous mice.

Methods: By gene targeting we have generated a mutant mice with a deletion of the first 140 amino-acids of TFII-I. mRNA and protein expression analysis were used to document the effect of the study deletion. We performed behavioral characterization of heterozygous mutant mice to document in vivo implications of TFII-I in the cognitive profile of WBS patients.

Results: Homozygous and heterozygous mutant mice exhibit craniofacial alterations, most clearly represented in homozygous condition. Behavioral test demonstrate that heterozygous mutant mice exhibit some neurobehavioral alterations and hyperacusis or odynacusis that could be associated with specific features of WBS phenotype. Homozygous mutant mice present highly compromised embryonic viability and fertility. Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs.

Conclusion: Our data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression of GTF2I is one of the main players. In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at the in vivo model.

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Neurobehavioral phenotype. A. Locomotor activity. A decrease in the vertical but not in horizontal locomotor activity measured in the actimetry box was observed in Gtf2i+/Δex2 mice (P = 0.03). B. Elevated Plus Maze. Higher anxiety level was manifested in the Gtf2i+/Δex2 indicated by the reduced percentage of entries in the open arms (P = 0.001) and in the time spent in open arms (P = 0.0089). C. Open Field . Histograms represent latency (in seconds) and the number of entries in central zone. D.Lit/dark box. Gtf2i+/Δex2 mice showed a higher anxiety level revealed by increased latency of the first entry (P = 0.01), the lower activity (P= 0.02) and the time spent into the lit compartment. E. Acoustic sensitivity. Enhanced sensitivity to an acute tone of 2800 Hz emitted at 65dB was observed in Gtf2i+/Δex2 mice demonstrated by a longer lasting freezing behavior (P = 0.01). Freezer response was similar between genotypes at 85, 105 and 125 dB confirming a plateau of response.Gtf2i+/+, open; Gtf2i+/Δex2, grey squares. Each genotype groups are composed by males (n = 15). All values are expressed as mean ± s.d.
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Figure 4: Neurobehavioral phenotype. A. Locomotor activity. A decrease in the vertical but not in horizontal locomotor activity measured in the actimetry box was observed in Gtf2i+/Δex2 mice (P = 0.03). B. Elevated Plus Maze. Higher anxiety level was manifested in the Gtf2i+/Δex2 indicated by the reduced percentage of entries in the open arms (P = 0.001) and in the time spent in open arms (P = 0.0089). C. Open Field . Histograms represent latency (in seconds) and the number of entries in central zone. D.Lit/dark box. Gtf2i+/Δex2 mice showed a higher anxiety level revealed by increased latency of the first entry (P = 0.01), the lower activity (P= 0.02) and the time spent into the lit compartment. E. Acoustic sensitivity. Enhanced sensitivity to an acute tone of 2800 Hz emitted at 65dB was observed in Gtf2i+/Δex2 mice demonstrated by a longer lasting freezing behavior (P = 0.01). Freezer response was similar between genotypes at 85, 105 and 125 dB confirming a plateau of response.Gtf2i+/+, open; Gtf2i+/Δex2, grey squares. Each genotype groups are composed by males (n = 15). All values are expressed as mean ± s.d.

Mentions: To evaluate a possible involvement of TFII-I in the psychomotor and neurobehavioral WBS phenotype, Gtf2i+/+, Gtf2i+/Δex2 mice (n = 15 males per group) were evaluated in several paradigms. Motor coordination (wire hanging), locomotor activity (actimetry boxes and open-field) and anxiety-related behaviors (lit-dark box; elevated plus maze) were first explored. A significant decrease in the vertical but not in horizontal locomotor activity (Figure 4A) was evident in Gtf2i+/Δex2 mice related to a decreased exploratory activity despite normal motor coordination (see Additional file 5).


Essential role of the N-terminal region of TFII-I in viability and behavior.

Lucena J, Pezzi S, Aso E, Valero MC, Carreiro C, Dubus P, Sampaio A, Segura M, Barthelemy I, Zindel MY, Sousa N, Barbero JL, Maldonado R, Pérez-Jurado LA, Campuzano V - BMC Med. Genet. (2010)

Neurobehavioral phenotype. A. Locomotor activity. A decrease in the vertical but not in horizontal locomotor activity measured in the actimetry box was observed in Gtf2i+/Δex2 mice (P = 0.03). B. Elevated Plus Maze. Higher anxiety level was manifested in the Gtf2i+/Δex2 indicated by the reduced percentage of entries in the open arms (P = 0.001) and in the time spent in open arms (P = 0.0089). C. Open Field . Histograms represent latency (in seconds) and the number of entries in central zone. D.Lit/dark box. Gtf2i+/Δex2 mice showed a higher anxiety level revealed by increased latency of the first entry (P = 0.01), the lower activity (P= 0.02) and the time spent into the lit compartment. E. Acoustic sensitivity. Enhanced sensitivity to an acute tone of 2800 Hz emitted at 65dB was observed in Gtf2i+/Δex2 mice demonstrated by a longer lasting freezing behavior (P = 0.01). Freezer response was similar between genotypes at 85, 105 and 125 dB confirming a plateau of response.Gtf2i+/+, open; Gtf2i+/Δex2, grey squares. Each genotype groups are composed by males (n = 15). All values are expressed as mean ± s.d.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2865459&req=5

Figure 4: Neurobehavioral phenotype. A. Locomotor activity. A decrease in the vertical but not in horizontal locomotor activity measured in the actimetry box was observed in Gtf2i+/Δex2 mice (P = 0.03). B. Elevated Plus Maze. Higher anxiety level was manifested in the Gtf2i+/Δex2 indicated by the reduced percentage of entries in the open arms (P = 0.001) and in the time spent in open arms (P = 0.0089). C. Open Field . Histograms represent latency (in seconds) and the number of entries in central zone. D.Lit/dark box. Gtf2i+/Δex2 mice showed a higher anxiety level revealed by increased latency of the first entry (P = 0.01), the lower activity (P= 0.02) and the time spent into the lit compartment. E. Acoustic sensitivity. Enhanced sensitivity to an acute tone of 2800 Hz emitted at 65dB was observed in Gtf2i+/Δex2 mice demonstrated by a longer lasting freezing behavior (P = 0.01). Freezer response was similar between genotypes at 85, 105 and 125 dB confirming a plateau of response.Gtf2i+/+, open; Gtf2i+/Δex2, grey squares. Each genotype groups are composed by males (n = 15). All values are expressed as mean ± s.d.
Mentions: To evaluate a possible involvement of TFII-I in the psychomotor and neurobehavioral WBS phenotype, Gtf2i+/+, Gtf2i+/Δex2 mice (n = 15 males per group) were evaluated in several paradigms. Motor coordination (wire hanging), locomotor activity (actimetry boxes and open-field) and anxiety-related behaviors (lit-dark box; elevated plus maze) were first explored. A significant decrease in the vertical but not in horizontal locomotor activity (Figure 4A) was evident in Gtf2i+/Δex2 mice related to a decreased exploratory activity despite normal motor coordination (see Additional file 5).

Bottom Line: Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs.Our data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression of GTF2I is one of the main players.In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at the in vivo model.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetics Unit, de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

ABSTRACT

Background: GTF2I codes for a general intrinsic transcription factor and calcium channel regulator TFII-I, with high and ubiquitous expression, and a strong candidate for involvement in the morphological and neuro-developmental anomalies of the Williams-Beuren syndrome (WBS). WBS is a genetic disorder due to a recurring deletion of about 1,55-1,83 Mb containing 25-28 genes in chromosome band 7q11.23 including GTF2I. Completed homozygous loss of either the Gtf2i or Gtf2ird1 function in mice provided additional evidence for the involvement of both genes in the craniofacial and cognitive phenotype. Unfortunately nothing is now about the behavioral characterization of heterozygous mice.

Methods: By gene targeting we have generated a mutant mice with a deletion of the first 140 amino-acids of TFII-I. mRNA and protein expression analysis were used to document the effect of the study deletion. We performed behavioral characterization of heterozygous mutant mice to document in vivo implications of TFII-I in the cognitive profile of WBS patients.

Results: Homozygous and heterozygous mutant mice exhibit craniofacial alterations, most clearly represented in homozygous condition. Behavioral test demonstrate that heterozygous mutant mice exhibit some neurobehavioral alterations and hyperacusis or odynacusis that could be associated with specific features of WBS phenotype. Homozygous mutant mice present highly compromised embryonic viability and fertility. Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs.

Conclusion: Our data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression of GTF2I is one of the main players. In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at the in vivo model.

Show MeSH
Related in: MedlinePlus