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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

Impaired memory in Srcthl/thl mutant mice. A, Mice were assessed in the Morris water maze procedure (n = 12 WT (12 males), n = 12 Srcthl/thl (12 males)). Mean latency to reach a target platform in a visible platform session (days 1 and 2), and in a hidden-platform acquisition phase (days 3-8). B, Spatial memory retention was assessed in the probe trials administered 2 h after day 8 (n = 12 WT (12 males), n = 12 Srcthl/thl (12 males)). Mean number of platform crosses during probe trial 1 are shown. *p < 0.05. C, Freezing (as a percentage of total time) in a novel conditioning chamber (n = 24 WT (13 males, 11 females), n = 22 Srcthl/thl (12 males, 10 females)). After recording baseline freezing for 120 s, a tone was presented for 30 s (novel tone), after which mice were given a footshock and left inside the chamber for another 30 s (after shock). A subtle increase in freezing was observed during baseline and novel tone presentation in Srcthl/thl mice. *p < 0.05. D, Cued fear memory 24 h after pairing (n = 24 WT (13 males, 11 females), n = 22 Srcthl/thl (12 males, 10 females)). Pre-CS is freezing in the absence of the tone in a novel context, while CS is percentage freezing during tone presentation. Srcthl/thl mice showed impaired auditory fear conditioning, however, context was not affected. Data are presented as mean ± SEM, *p < 0.05.
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Figure 7: Impaired memory in Srcthl/thl mutant mice. A, Mice were assessed in the Morris water maze procedure (n = 12 WT (12 males), n = 12 Srcthl/thl (12 males)). Mean latency to reach a target platform in a visible platform session (days 1 and 2), and in a hidden-platform acquisition phase (days 3-8). B, Spatial memory retention was assessed in the probe trials administered 2 h after day 8 (n = 12 WT (12 males), n = 12 Srcthl/thl (12 males)). Mean number of platform crosses during probe trial 1 are shown. *p < 0.05. C, Freezing (as a percentage of total time) in a novel conditioning chamber (n = 24 WT (13 males, 11 females), n = 22 Srcthl/thl (12 males, 10 females)). After recording baseline freezing for 120 s, a tone was presented for 30 s (novel tone), after which mice were given a footshock and left inside the chamber for another 30 s (after shock). A subtle increase in freezing was observed during baseline and novel tone presentation in Srcthl/thl mice. *p < 0.05. D, Cued fear memory 24 h after pairing (n = 24 WT (13 males, 11 females), n = 22 Srcthl/thl (12 males, 10 females)). Pre-CS is freezing in the absence of the tone in a novel context, while CS is percentage freezing during tone presentation. Srcthl/thl mice showed impaired auditory fear conditioning, however, context was not affected. Data are presented as mean ± SEM, *p < 0.05.

Mentions: Visuospatial learning and memory was assessed using the Morris water maze task. Srcthl/thl mice did not show impaired motor performance or decreased motivation to escape, as all mutants showed similar escape latencies in the visible and the hidden platform task (p = 0.4648, two-way ANOVA) (Fig. 7A).There was a significant effect of genotype (p = 0.001, F(1,22) = 22.32) but no effect of target (p = 0.3926, F(1,22) = 0.76) (two-way ANOVA) in the probe trial given after 6 d of training. WT mice showed significantly more crossings of the target platform position compared with similarly sized and positioned areas in the other quadrants (crossing in target platform quadrant: 4.42 ± 0.514, averaged crossing in nontarget quadrants: 2.72 ± 0.27, p = 0.0082, F(1,22) = 8.44), whereas Srcthl/thl mice did not show any preference for the target location (crossing in target platform quadrant: 1.42 ± 0.42, averaged crossing in nontarget quadrants: 2.33 ± 0.38, p = 0.1167, F(1,22) = 2.67) (Fig. 7B).


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)

Impaired memory in Srcthl/thl mutant mice. A, Mice were assessed in the Morris water maze procedure (n = 12 WT (12 males), n = 12 Srcthl/thl (12 males)). Mean latency to reach a target platform in a visible platform session (days 1 and 2), and in a hidden-platform acquisition phase (days 3-8). B, Spatial memory retention was assessed in the probe trials administered 2 h after day 8 (n = 12 WT (12 males), n = 12 Srcthl/thl (12 males)). Mean number of platform crosses during probe trial 1 are shown. *p < 0.05. C, Freezing (as a percentage of total time) in a novel conditioning chamber (n = 24 WT (13 males, 11 females), n = 22 Srcthl/thl (12 males, 10 females)). After recording baseline freezing for 120 s, a tone was presented for 30 s (novel tone), after which mice were given a footshock and left inside the chamber for another 30 s (after shock). A subtle increase in freezing was observed during baseline and novel tone presentation in Srcthl/thl mice. *p < 0.05. D, Cued fear memory 24 h after pairing (n = 24 WT (13 males, 11 females), n = 22 Srcthl/thl (12 males, 10 females)). Pre-CS is freezing in the absence of the tone in a novel context, while CS is percentage freezing during tone presentation. Srcthl/thl mice showed impaired auditory fear conditioning, however, context was not affected. Data are presented as mean ± SEM, *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Impaired memory in Srcthl/thl mutant mice. A, Mice were assessed in the Morris water maze procedure (n = 12 WT (12 males), n = 12 Srcthl/thl (12 males)). Mean latency to reach a target platform in a visible platform session (days 1 and 2), and in a hidden-platform acquisition phase (days 3-8). B, Spatial memory retention was assessed in the probe trials administered 2 h after day 8 (n = 12 WT (12 males), n = 12 Srcthl/thl (12 males)). Mean number of platform crosses during probe trial 1 are shown. *p < 0.05. C, Freezing (as a percentage of total time) in a novel conditioning chamber (n = 24 WT (13 males, 11 females), n = 22 Srcthl/thl (12 males, 10 females)). After recording baseline freezing for 120 s, a tone was presented for 30 s (novel tone), after which mice were given a footshock and left inside the chamber for another 30 s (after shock). A subtle increase in freezing was observed during baseline and novel tone presentation in Srcthl/thl mice. *p < 0.05. D, Cued fear memory 24 h after pairing (n = 24 WT (13 males, 11 females), n = 22 Srcthl/thl (12 males, 10 females)). Pre-CS is freezing in the absence of the tone in a novel context, while CS is percentage freezing during tone presentation. Srcthl/thl mice showed impaired auditory fear conditioning, however, context was not affected. Data are presented as mean ± SEM, *p < 0.05.
Mentions: Visuospatial learning and memory was assessed using the Morris water maze task. Srcthl/thl mice did not show impaired motor performance or decreased motivation to escape, as all mutants showed similar escape latencies in the visible and the hidden platform task (p = 0.4648, two-way ANOVA) (Fig. 7A).There was a significant effect of genotype (p = 0.001, F(1,22) = 22.32) but no effect of target (p = 0.3926, F(1,22) = 0.76) (two-way ANOVA) in the probe trial given after 6 d of training. WT mice showed significantly more crossings of the target platform position compared with similarly sized and positioned areas in the other quadrants (crossing in target platform quadrant: 4.42 ± 0.514, averaged crossing in nontarget quadrants: 2.72 ± 0.27, p = 0.0082, F(1,22) = 8.44), whereas Srcthl/thl mice did not show any preference for the target location (crossing in target platform quadrant: 1.42 ± 0.42, averaged crossing in nontarget quadrants: 2.33 ± 0.38, p = 0.1167, F(1,22) = 2.67) (Fig. 7B).

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