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Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I(1,2).

Sinai L, Ivakine EA, Lam E, Deurloo M, Dida J, Zirngibl RA, Jung C, Aubin JE, Feng ZP, Yeomans J, McInnes RR, Osborne LR, Roder JC - eNeuro (2015)

Bottom Line: Src is a nonreceptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions.Src phosphorylation regulates the movement of GTF2I protein (TFII-I) between the nucleus, where it is a transcriptional activator, and the cytoplasm, where it regulates trafficking of transient receptor potential cation channel, subfamily C, member 3 (TRPC3) subunits to the plasma membrane.Here, we demonstrate altered cellular localization of both TFII-I and TRPC3 in the Src mutants, suggesting that disruption of Src can phenocopy behavioral phenotypes observed in WBS through its regulation of TFII-I.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Medical Science, University of Toronto , Toronto, Ontario, M5S 1A8, Canada ; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto Ontario, M5S 3E1, Canada.

ABSTRACT
Src is a nonreceptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions. Mice homozygous for a spontaneous mutation in Src (Src (thl/thl) ) exhibited hypersociability and hyperactivity along with impairments in visuospatial, amygdala-dependent, and motor learning as well as an increased startle response to loud tones. The phenotype of Src (thl/thl) mice showed significant overlap with Williams-Beuren syndrome (WBS), a disorder caused by the deletion of several genes, including General Transcription Factor 2-I (GTF2I). Src phosphorylation regulates the movement of GTF2I protein (TFII-I) between the nucleus, where it is a transcriptional activator, and the cytoplasm, where it regulates trafficking of transient receptor potential cation channel, subfamily C, member 3 (TRPC3) subunits to the plasma membrane. Here, we demonstrate altered cellular localization of both TFII-I and TRPC3 in the Src mutants, suggesting that disruption of Src can phenocopy behavioral phenotypes observed in WBS through its regulation of TFII-I.

No MeSH data available.


Related in: MedlinePlus

Srcthl/thl mutant mice show hyperactivity in the open field. A, Srcthl/thl mutant mice showed an increase in total distance travelled in the open field compared with WT mice (n = 10 WT (5 males, 5 females), n = 16 Srcthl/thl (9 males, 7 females)). B, Percentage of time spent in the center of the arena versus the entire open field was decreased in Srcthl/thl (n = 10 WT (5 males, 5 females), n = 16 Srcthl/thl (9 males, 7 females)). *p < 0.05 between genotypes. C, Percentage time spent in the open arms versus the closed arms of the elevated plus maze showed no significant differences between genotypes (n = 13 WT (7 males, 6 females), n = 18 Srcthl/thl (9 males, 9 females)). Data are presented as mean ± SEM.
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Figure 4: Srcthl/thl mutant mice show hyperactivity in the open field. A, Srcthl/thl mutant mice showed an increase in total distance travelled in the open field compared with WT mice (n = 10 WT (5 males, 5 females), n = 16 Srcthl/thl (9 males, 7 females)). B, Percentage of time spent in the center of the arena versus the entire open field was decreased in Srcthl/thl (n = 10 WT (5 males, 5 females), n = 16 Srcthl/thl (9 males, 7 females)). *p < 0.05 between genotypes. C, Percentage time spent in the open arms versus the closed arms of the elevated plus maze showed no significant differences between genotypes (n = 13 WT (7 males, 6 females), n = 18 Srcthl/thl (9 males, 9 females)). Data are presented as mean ± SEM.

Mentions: In the open-field test, there was a significant effect of genotype (p = 0.0381, F(1,170) = 4.66) and time interval (p = 0.0006, F(5,170) = 4.54) on the total distance travelled (Fig. 4A), with the Srcthl/thl mice having a greater total distance travelled and both genotypes travelling more during the first 15 min. Srcthl/thl mice travelled less distance in the center of the arena compared with WT mice (WT = 31.19 ± 6.76%; Srcthl/thl = 12.89 ± 3.16%, p = 0.011, F(1,24) = 7.59, one-way ANOVA) (Fig. 4B), suggesting an increase in anxiety-like behavior in the Srcthl/thl mice. However, we did not observe any difference between genotypes in the elevated plus maze, another test for anxiety. The percentage time spent in the open arm was similar in both groups (WT = 4.11 ± 1.17%; Srcthl/thl = 4.64 ± 1.35%, p = 0.7775, F(1,29) = 0.08, one-way ANOVA) (Fig. 4C). The total distance travelled in the elevated plus maze was not different between the two genotypes.


Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I(1,2).

Sinai L, Ivakine EA, Lam E, Deurloo M, Dida J, Zirngibl RA, Jung C, Aubin JE, Feng ZP, Yeomans J, McInnes RR, Osborne LR, Roder JC - eNeuro (2015)

Srcthl/thl mutant mice show hyperactivity in the open field. A, Srcthl/thl mutant mice showed an increase in total distance travelled in the open field compared with WT mice (n = 10 WT (5 males, 5 females), n = 16 Srcthl/thl (9 males, 7 females)). B, Percentage of time spent in the center of the arena versus the entire open field was decreased in Srcthl/thl (n = 10 WT (5 males, 5 females), n = 16 Srcthl/thl (9 males, 7 females)). *p < 0.05 between genotypes. C, Percentage time spent in the open arms versus the closed arms of the elevated plus maze showed no significant differences between genotypes (n = 13 WT (7 males, 6 females), n = 18 Srcthl/thl (9 males, 9 females)). Data are presented as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596087&req=5

Figure 4: Srcthl/thl mutant mice show hyperactivity in the open field. A, Srcthl/thl mutant mice showed an increase in total distance travelled in the open field compared with WT mice (n = 10 WT (5 males, 5 females), n = 16 Srcthl/thl (9 males, 7 females)). B, Percentage of time spent in the center of the arena versus the entire open field was decreased in Srcthl/thl (n = 10 WT (5 males, 5 females), n = 16 Srcthl/thl (9 males, 7 females)). *p < 0.05 between genotypes. C, Percentage time spent in the open arms versus the closed arms of the elevated plus maze showed no significant differences between genotypes (n = 13 WT (7 males, 6 females), n = 18 Srcthl/thl (9 males, 9 females)). Data are presented as mean ± SEM.
Mentions: In the open-field test, there was a significant effect of genotype (p = 0.0381, F(1,170) = 4.66) and time interval (p = 0.0006, F(5,170) = 4.54) on the total distance travelled (Fig. 4A), with the Srcthl/thl mice having a greater total distance travelled and both genotypes travelling more during the first 15 min. Srcthl/thl mice travelled less distance in the center of the arena compared with WT mice (WT = 31.19 ± 6.76%; Srcthl/thl = 12.89 ± 3.16%, p = 0.011, F(1,24) = 7.59, one-way ANOVA) (Fig. 4B), suggesting an increase in anxiety-like behavior in the Srcthl/thl mice. However, we did not observe any difference between genotypes in the elevated plus maze, another test for anxiety. The percentage time spent in the open arm was similar in both groups (WT = 4.11 ± 1.17%; Srcthl/thl = 4.64 ± 1.35%, p = 0.7775, F(1,29) = 0.08, one-way ANOVA) (Fig. 4C). The total distance travelled in the elevated plus maze was not different between the two genotypes.

Bottom Line: Src is a nonreceptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions.Src phosphorylation regulates the movement of GTF2I protein (TFII-I) between the nucleus, where it is a transcriptional activator, and the cytoplasm, where it regulates trafficking of transient receptor potential cation channel, subfamily C, member 3 (TRPC3) subunits to the plasma membrane.Here, we demonstrate altered cellular localization of both TFII-I and TRPC3 in the Src mutants, suggesting that disruption of Src can phenocopy behavioral phenotypes observed in WBS through its regulation of TFII-I.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Medical Science, University of Toronto , Toronto, Ontario, M5S 1A8, Canada ; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto Ontario, M5S 3E1, Canada.

ABSTRACT
Src is a nonreceptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions. Mice homozygous for a spontaneous mutation in Src (Src (thl/thl) ) exhibited hypersociability and hyperactivity along with impairments in visuospatial, amygdala-dependent, and motor learning as well as an increased startle response to loud tones. The phenotype of Src (thl/thl) mice showed significant overlap with Williams-Beuren syndrome (WBS), a disorder caused by the deletion of several genes, including General Transcription Factor 2-I (GTF2I). Src phosphorylation regulates the movement of GTF2I protein (TFII-I) between the nucleus, where it is a transcriptional activator, and the cytoplasm, where it regulates trafficking of transient receptor potential cation channel, subfamily C, member 3 (TRPC3) subunits to the plasma membrane. Here, we demonstrate altered cellular localization of both TFII-I and TRPC3 in the Src mutants, suggesting that disruption of Src can phenocopy behavioral phenotypes observed in WBS through its regulation of TFII-I.

No MeSH data available.


Related in: MedlinePlus