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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

Acoustic startle in response to high startling stimulus is increased in Srcthl/thl mice. Both the WT and Srcthl/thl mice exhibited similar startle amplitude responses to the low-intensity acoustic stimuli (70-105 dB). Srcthl/thl mice showed higher responses to the high-intensity stimuli (110-115 dB) (n = 8 WT (8 males), n = 8 Srcthl/thl (18 males)). *p < 0.05.
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Figure 6: Acoustic startle in response to high startling stimulus is increased in Srcthl/thl mice. Both the WT and Srcthl/thl mice exhibited similar startle amplitude responses to the low-intensity acoustic stimuli (70-105 dB). Srcthl/thl mice showed higher responses to the high-intensity stimuli (110-115 dB) (n = 8 WT (8 males), n = 8 Srcthl/thl (18 males)). *p < 0.05.

Mentions: Srcthl/thl mice showed a significant enhancement of startle response at the 115 dB (WT = 242.0 ± 41.36 AU; Srcthl/thl = 471.1 ± 83.82 AU, p = 0.028, F(1,14) = 6.01) and 110 dB (WT = 293.2 ± 13.69 AU; Srcthl/thl = 410.3 ± 36.92 AU, p = 0.01, F(1,14) = 8.85) levels of startling stimulus. However, at the 70-105 dB levels, Srcthl/thl mice exhibited a similar startle magnitude when compared with WT mice (p = 0.05) (one-way ANOVA) (Fig. 6).


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)

Acoustic startle in response to high startling stimulus is increased in Srcthl/thl mice. Both the WT and Srcthl/thl mice exhibited similar startle amplitude responses to the low-intensity acoustic stimuli (70-105 dB). Srcthl/thl mice showed higher responses to the high-intensity stimuli (110-115 dB) (n = 8 WT (8 males), n = 8 Srcthl/thl (18 males)). *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Acoustic startle in response to high startling stimulus is increased in Srcthl/thl mice. Both the WT and Srcthl/thl mice exhibited similar startle amplitude responses to the low-intensity acoustic stimuli (70-105 dB). Srcthl/thl mice showed higher responses to the high-intensity stimuli (110-115 dB) (n = 8 WT (8 males), n = 8 Srcthl/thl (18 males)). *p < 0.05.
Mentions: Srcthl/thl mice showed a significant enhancement of startle response at the 115 dB (WT = 242.0 ± 41.36 AU; Srcthl/thl = 471.1 ± 83.82 AU, p = 0.028, F(1,14) = 6.01) and 110 dB (WT = 293.2 ± 13.69 AU; Srcthl/thl = 410.3 ± 36.92 AU, p = 0.01, F(1,14) = 8.85) levels of startling stimulus. However, at the 70-105 dB levels, Srcthl/thl mice exhibited a similar startle magnitude when compared with WT mice (p = 0.05) (one-way ANOVA) (Fig. 6).

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