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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

Social approach behaviors are increased and social recognition is impaired in Srcthl/thl mice. A, Srcthl/thl mice spent more time sniffing a social cage versus a nonsocial cage (n = 9 WT males, n = 8 Srcthl/thl males). B, During the second phase of the test to measure social recognition, Srcthl/thl mice did not show a preference for a novel mouse versus a familiar mouse from the first phase (n = 9 WT males, n = 8 Srcthl/thl males). *p < 0.05, compared to the chamber with empty cage, between genotypes and within genotypes, respectively. C, In a direct social interaction test, Srcthl/thl mice showed an increased frequency of interactions with a stranger mouse. Data are presented as mean ± SEM (n = 9 WT males, n = 8 Srcthl/thl males). *p < 0.05, between genotypes. D, Srcthl/thl mice showed social dominance over their WT littermates in a tube test (n = 20 WT males, n = 20 Srcthl/thl males). *p < 0.05, between genotypes. E, Srcthl/thl mice were able to habituate to a smell over time and dishabituate toward a novel smell, demonstrating intact olfaction (n = 10 WT (5 males, 5 females), n = 9 Srcthl/thl (5 males, 4 females)). Data are presented as mean ± SEM.
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Figure 2: Social approach behaviors are increased and social recognition is impaired in Srcthl/thl mice. A, Srcthl/thl mice spent more time sniffing a social cage versus a nonsocial cage (n = 9 WT males, n = 8 Srcthl/thl males). B, During the second phase of the test to measure social recognition, Srcthl/thl mice did not show a preference for a novel mouse versus a familiar mouse from the first phase (n = 9 WT males, n = 8 Srcthl/thl males). *p < 0.05, compared to the chamber with empty cage, between genotypes and within genotypes, respectively. C, In a direct social interaction test, Srcthl/thl mice showed an increased frequency of interactions with a stranger mouse. Data are presented as mean ± SEM (n = 9 WT males, n = 8 Srcthl/thl males). *p < 0.05, between genotypes. D, Srcthl/thl mice showed social dominance over their WT littermates in a tube test (n = 20 WT males, n = 20 Srcthl/thl males). *p < 0.05, between genotypes. E, Srcthl/thl mice were able to habituate to a smell over time and dishabituate toward a novel smell, demonstrating intact olfaction (n = 10 WT (5 males, 5 females), n = 9 Srcthl/thl (5 males, 4 females)). Data are presented as mean ± SEM.

Mentions: We used a three-chambered apparatus in which mice were tested in two different trials. In the first trial, the subject mouse was given the choice to spend time with a social object (mouse) or spend time with a nonsocial object (empty). There was a statistically significant interaction between social versus nonsocial object and genotype (p = 0.0089, F(1,15) = 9.02). The effect of genotype was not quite significant (p = 0.052, F(1,15) = 4.42). The effect of social versus nonsocial object was highly significant (p = 0.0001, F(1,15) = 50.85). Both Srcthl/thl and WT mice showed a preference for the mouse (time with mouse vs nonsocial object: WT: p = 0.0082, F(1,16) = 9.11; Srcthl/thl mice: p = 0.0001, F(1,14) = 40.42), but the Srcthl/thl mice spent significantly more time with the mouse compared to WT mice (WT = 180.6 s ± 30.89, Srcthl/thl = 310.6 s ± 34.91, p = 0.0135, F(1,14) = 7.8) (Fig. 2A). However, in the test for social novelty preference, only WT mice showed a significant preference for a nonfamiliar mouse (Mouse 2) in comparison with time spent with a familiar mouse (Mouse 1) (time for Mouse 1: Srcthl/thl = 60.90 s ± 13.10; time for Mouse 2: Srcthl/thl = 153.1 s ± 26.30, p = 0.0063, F(1,16) = 9.85) (Fig. 2B). Srcthl/thl mice were not able to distinguish between Mouse 1 and Mouse 2, suggesting impairment in short term social recognition in Srcthl/thl mice (time for familiar mouse: Srcthl/thl = 192.8 s ± 29.00, time for nonfamiliar mouse: Srcthl/thl = 141.0 s ± 27.56, p = 0.2165, F(1,14) = 1.68) (Fig. 2B). Number of entries into each compartment was not different between genotypes in each session.


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)

Social approach behaviors are increased and social recognition is impaired in Srcthl/thl mice. A, Srcthl/thl mice spent more time sniffing a social cage versus a nonsocial cage (n = 9 WT males, n = 8 Srcthl/thl males). B, During the second phase of the test to measure social recognition, Srcthl/thl mice did not show a preference for a novel mouse versus a familiar mouse from the first phase (n = 9 WT males, n = 8 Srcthl/thl males). *p < 0.05, compared to the chamber with empty cage, between genotypes and within genotypes, respectively. C, In a direct social interaction test, Srcthl/thl mice showed an increased frequency of interactions with a stranger mouse. Data are presented as mean ± SEM (n = 9 WT males, n = 8 Srcthl/thl males). *p < 0.05, between genotypes. D, Srcthl/thl mice showed social dominance over their WT littermates in a tube test (n = 20 WT males, n = 20 Srcthl/thl males). *p < 0.05, between genotypes. E, Srcthl/thl mice were able to habituate to a smell over time and dishabituate toward a novel smell, demonstrating intact olfaction (n = 10 WT (5 males, 5 females), n = 9 Srcthl/thl (5 males, 4 females)). Data are presented as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Social approach behaviors are increased and social recognition is impaired in Srcthl/thl mice. A, Srcthl/thl mice spent more time sniffing a social cage versus a nonsocial cage (n = 9 WT males, n = 8 Srcthl/thl males). B, During the second phase of the test to measure social recognition, Srcthl/thl mice did not show a preference for a novel mouse versus a familiar mouse from the first phase (n = 9 WT males, n = 8 Srcthl/thl males). *p < 0.05, compared to the chamber with empty cage, between genotypes and within genotypes, respectively. C, In a direct social interaction test, Srcthl/thl mice showed an increased frequency of interactions with a stranger mouse. Data are presented as mean ± SEM (n = 9 WT males, n = 8 Srcthl/thl males). *p < 0.05, between genotypes. D, Srcthl/thl mice showed social dominance over their WT littermates in a tube test (n = 20 WT males, n = 20 Srcthl/thl males). *p < 0.05, between genotypes. E, Srcthl/thl mice were able to habituate to a smell over time and dishabituate toward a novel smell, demonstrating intact olfaction (n = 10 WT (5 males, 5 females), n = 9 Srcthl/thl (5 males, 4 females)). Data are presented as mean ± SEM.
Mentions: We used a three-chambered apparatus in which mice were tested in two different trials. In the first trial, the subject mouse was given the choice to spend time with a social object (mouse) or spend time with a nonsocial object (empty). There was a statistically significant interaction between social versus nonsocial object and genotype (p = 0.0089, F(1,15) = 9.02). The effect of genotype was not quite significant (p = 0.052, F(1,15) = 4.42). The effect of social versus nonsocial object was highly significant (p = 0.0001, F(1,15) = 50.85). Both Srcthl/thl and WT mice showed a preference for the mouse (time with mouse vs nonsocial object: WT: p = 0.0082, F(1,16) = 9.11; Srcthl/thl mice: p = 0.0001, F(1,14) = 40.42), but the Srcthl/thl mice spent significantly more time with the mouse compared to WT mice (WT = 180.6 s ± 30.89, Srcthl/thl = 310.6 s ± 34.91, p = 0.0135, F(1,14) = 7.8) (Fig. 2A). However, in the test for social novelty preference, only WT mice showed a significant preference for a nonfamiliar mouse (Mouse 2) in comparison with time spent with a familiar mouse (Mouse 1) (time for Mouse 1: Srcthl/thl = 60.90 s ± 13.10; time for Mouse 2: Srcthl/thl = 153.1 s ± 26.30, p = 0.0063, F(1,16) = 9.85) (Fig. 2B). Srcthl/thl mice were not able to distinguish between Mouse 1 and Mouse 2, suggesting impairment in short term social recognition in Srcthl/thl mice (time for familiar mouse: Srcthl/thl = 192.8 s ± 29.00, time for nonfamiliar mouse: Srcthl/thl = 141.0 s ± 27.56, p = 0.2165, F(1,14) = 1.68) (Fig. 2B). Number of entries into each compartment was not different between genotypes in each session.

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