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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

Balance and motor strength deficiency in Srcthl/thl mice and the inability to learn motor skills. Quantitative analysis of raised balance beam, grip strength, and rotarod task in WT and Srcthl/thl mice. A, Srcthl/thl mice needed significantly more time to cross the balance beam than did WT mice (n = 13 WT (7 males, 6 females), n = 12 Srcthl/thl (6 males, 6 females)). B, Srcthl/thl mice had significantly more hindfoot slips than did WT mice. C, Grip strength analysis revealed significantly reduced forelimb grip strength in Srcthl/thl mice compared with WT animals (n = 16 WT (9 males, 7 females), n = 12 Srcthl/thl (6 males, 6 females)). D, Grip strength analysis revealed significantly reduced combined forelimb and hindlimb grip strength in Srcthl/thl mice compared with WT animals (n = 16 WT (9 males, 7 females), n = 12 Srcthl/thl (6 males, 6 females)). E, Mice were tested on an accelerating rotarod with the same speed for 4 consecutive days. The latencies from rotation onset until the mice fell off the rod were measured. WT mice managed to stay significantly longer on the accelerating rotarod than Srcthl/thl mice on days 3 and 4. The falling latencies were similar in both groups on days 1 and 2. Falling latencies were compared within genotype between days 1 and 4 (n = 12 WT (6 males, 6 females), n = 12 Srcthl/thl (6 males, 6 females)). Data are presented as mean ± SEM. *p < 0.05.
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Figure 5: Balance and motor strength deficiency in Srcthl/thl mice and the inability to learn motor skills. Quantitative analysis of raised balance beam, grip strength, and rotarod task in WT and Srcthl/thl mice. A, Srcthl/thl mice needed significantly more time to cross the balance beam than did WT mice (n = 13 WT (7 males, 6 females), n = 12 Srcthl/thl (6 males, 6 females)). B, Srcthl/thl mice had significantly more hindfoot slips than did WT mice. C, Grip strength analysis revealed significantly reduced forelimb grip strength in Srcthl/thl mice compared with WT animals (n = 16 WT (9 males, 7 females), n = 12 Srcthl/thl (6 males, 6 females)). D, Grip strength analysis revealed significantly reduced combined forelimb and hindlimb grip strength in Srcthl/thl mice compared with WT animals (n = 16 WT (9 males, 7 females), n = 12 Srcthl/thl (6 males, 6 females)). E, Mice were tested on an accelerating rotarod with the same speed for 4 consecutive days. The latencies from rotation onset until the mice fell off the rod were measured. WT mice managed to stay significantly longer on the accelerating rotarod than Srcthl/thl mice on days 3 and 4. The falling latencies were similar in both groups on days 1 and 2. Falling latencies were compared within genotype between days 1 and 4 (n = 12 WT (6 males, 6 females), n = 12 Srcthl/thl (6 males, 6 females)). Data are presented as mean ± SEM. *p < 0.05.

Mentions: We assessed motor coordination, strength, and motor skill learning in Srcthl/thl mice using the balance beam, grip strength, and rotarod tasks. Srcthl/thl mice took significantly longer time to cross the beam (WT = 5.54 ± 0.84 s; Srcthl/thl =11.50 ± 1.39 s, p = 0.0011, F(1,23) = 13.93) and had increased number of foot slips while crossing the beam (WT = 0.50 ± 0.23; Srcthl/thl =1.92 ± 0.31, p = 0.0014, F(1,23) = 13.30) (Fig. 5A,B) (one-way ANOVA).


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)

Balance and motor strength deficiency in Srcthl/thl mice and the inability to learn motor skills. Quantitative analysis of raised balance beam, grip strength, and rotarod task in WT and Srcthl/thl mice. A, Srcthl/thl mice needed significantly more time to cross the balance beam than did WT mice (n = 13 WT (7 males, 6 females), n = 12 Srcthl/thl (6 males, 6 females)). B, Srcthl/thl mice had significantly more hindfoot slips than did WT mice. C, Grip strength analysis revealed significantly reduced forelimb grip strength in Srcthl/thl mice compared with WT animals (n = 16 WT (9 males, 7 females), n = 12 Srcthl/thl (6 males, 6 females)). D, Grip strength analysis revealed significantly reduced combined forelimb and hindlimb grip strength in Srcthl/thl mice compared with WT animals (n = 16 WT (9 males, 7 females), n = 12 Srcthl/thl (6 males, 6 females)). E, Mice were tested on an accelerating rotarod with the same speed for 4 consecutive days. The latencies from rotation onset until the mice fell off the rod were measured. WT mice managed to stay significantly longer on the accelerating rotarod than Srcthl/thl mice on days 3 and 4. The falling latencies were similar in both groups on days 1 and 2. Falling latencies were compared within genotype between days 1 and 4 (n = 12 WT (6 males, 6 females), n = 12 Srcthl/thl (6 males, 6 females)). Data are presented as mean ± SEM. *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Balance and motor strength deficiency in Srcthl/thl mice and the inability to learn motor skills. Quantitative analysis of raised balance beam, grip strength, and rotarod task in WT and Srcthl/thl mice. A, Srcthl/thl mice needed significantly more time to cross the balance beam than did WT mice (n = 13 WT (7 males, 6 females), n = 12 Srcthl/thl (6 males, 6 females)). B, Srcthl/thl mice had significantly more hindfoot slips than did WT mice. C, Grip strength analysis revealed significantly reduced forelimb grip strength in Srcthl/thl mice compared with WT animals (n = 16 WT (9 males, 7 females), n = 12 Srcthl/thl (6 males, 6 females)). D, Grip strength analysis revealed significantly reduced combined forelimb and hindlimb grip strength in Srcthl/thl mice compared with WT animals (n = 16 WT (9 males, 7 females), n = 12 Srcthl/thl (6 males, 6 females)). E, Mice were tested on an accelerating rotarod with the same speed for 4 consecutive days. The latencies from rotation onset until the mice fell off the rod were measured. WT mice managed to stay significantly longer on the accelerating rotarod than Srcthl/thl mice on days 3 and 4. The falling latencies were similar in both groups on days 1 and 2. Falling latencies were compared within genotype between days 1 and 4 (n = 12 WT (6 males, 6 females), n = 12 Srcthl/thl (6 males, 6 females)). Data are presented as mean ± SEM. *p < 0.05.
Mentions: We assessed motor coordination, strength, and motor skill learning in Srcthl/thl mice using the balance beam, grip strength, and rotarod tasks. Srcthl/thl mice took significantly longer time to cross the beam (WT = 5.54 ± 0.84 s; Srcthl/thl =11.50 ± 1.39 s, p = 0.0011, F(1,23) = 13.93) and had increased number of foot slips while crossing the beam (WT = 0.50 ± 0.23; Srcthl/thl =1.92 ± 0.31, p = 0.0014, F(1,23) = 13.30) (Fig. 5A,B) (one-way ANOVA).

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