Limits...
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

Enhanced social reunion of female Srcthl/thl mutant mice. A, Time course of total number of USVs in WT and Srcthl/thl male mice when introduced to females for a 5 min trial. A gradual decline in total number of calls was observed across time but the total number of calls was still high, with no significant difference between WT and Srcthl/thl mice. Data are presented as mean ± SEM for each time point (n = 10 WT, n = 11 Srcthl/thl). B, Time course of total number of USVs in WT and Srcthl/thl females when reunited with a litter mate for a 5 min trial. A gradual decline in total number of calls is observed across time with a significant difference between WT and Srcthl/thl females in total number of USVs produced in the first and second minutes (n = 11 WT, n = 10 Srcthl/thl). C, There is a significant difference in the number of flat (Type 1) USVs produced by WT versus Srcthl/thl females at minute 1 (n = 11 WT, n = 10 Srcthl/thl). D, There was no significant difference in the number of broken (Type 2) USVs produced by WT versus Srcthl/thl females across time (n = 11 WT, n = 10 Srcthl/thl). E, There is a significant difference in the number of frequency modulated (Type 3) USVs produced by WT versus Srcthl/thl females at minutes 1 and 2 (n = 11 WT, n = 10 Srcthl/thl). Data are presented as mean ± SEM for each time point. *p < 0.05 between genotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4596087&req=5

Figure 3: Enhanced social reunion of female Srcthl/thl mutant mice. A, Time course of total number of USVs in WT and Srcthl/thl male mice when introduced to females for a 5 min trial. A gradual decline in total number of calls was observed across time but the total number of calls was still high, with no significant difference between WT and Srcthl/thl mice. Data are presented as mean ± SEM for each time point (n = 10 WT, n = 11 Srcthl/thl). B, Time course of total number of USVs in WT and Srcthl/thl females when reunited with a litter mate for a 5 min trial. A gradual decline in total number of calls is observed across time with a significant difference between WT and Srcthl/thl females in total number of USVs produced in the first and second minutes (n = 11 WT, n = 10 Srcthl/thl). C, There is a significant difference in the number of flat (Type 1) USVs produced by WT versus Srcthl/thl females at minute 1 (n = 11 WT, n = 10 Srcthl/thl). D, There was no significant difference in the number of broken (Type 2) USVs produced by WT versus Srcthl/thl females across time (n = 11 WT, n = 10 Srcthl/thl). E, There is a significant difference in the number of frequency modulated (Type 3) USVs produced by WT versus Srcthl/thl females at minutes 1 and 2 (n = 11 WT, n = 10 Srcthl/thl). Data are presented as mean ± SEM for each time point. *p < 0.05 between genotypes.

Mentions: Srcthl/thl and WT male mice emitted similar numbers of ultrasonic calls during the 5 min encounter with a female mouse. Repeated-measure ANOVA revealed no significant difference between groups across time (p = 0.4512) (Fig. 3A).


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)

Enhanced social reunion of female Srcthl/thl mutant mice. A, Time course of total number of USVs in WT and Srcthl/thl male mice when introduced to females for a 5 min trial. A gradual decline in total number of calls was observed across time but the total number of calls was still high, with no significant difference between WT and Srcthl/thl mice. Data are presented as mean ± SEM for each time point (n = 10 WT, n = 11 Srcthl/thl). B, Time course of total number of USVs in WT and Srcthl/thl females when reunited with a litter mate for a 5 min trial. A gradual decline in total number of calls is observed across time with a significant difference between WT and Srcthl/thl females in total number of USVs produced in the first and second minutes (n = 11 WT, n = 10 Srcthl/thl). C, There is a significant difference in the number of flat (Type 1) USVs produced by WT versus Srcthl/thl females at minute 1 (n = 11 WT, n = 10 Srcthl/thl). D, There was no significant difference in the number of broken (Type 2) USVs produced by WT versus Srcthl/thl females across time (n = 11 WT, n = 10 Srcthl/thl). E, There is a significant difference in the number of frequency modulated (Type 3) USVs produced by WT versus Srcthl/thl females at minutes 1 and 2 (n = 11 WT, n = 10 Srcthl/thl). Data are presented as mean ± SEM for each time point. *p < 0.05 between genotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Enhanced social reunion of female Srcthl/thl mutant mice. A, Time course of total number of USVs in WT and Srcthl/thl male mice when introduced to females for a 5 min trial. A gradual decline in total number of calls was observed across time but the total number of calls was still high, with no significant difference between WT and Srcthl/thl mice. Data are presented as mean ± SEM for each time point (n = 10 WT, n = 11 Srcthl/thl). B, Time course of total number of USVs in WT and Srcthl/thl females when reunited with a litter mate for a 5 min trial. A gradual decline in total number of calls is observed across time with a significant difference between WT and Srcthl/thl females in total number of USVs produced in the first and second minutes (n = 11 WT, n = 10 Srcthl/thl). C, There is a significant difference in the number of flat (Type 1) USVs produced by WT versus Srcthl/thl females at minute 1 (n = 11 WT, n = 10 Srcthl/thl). D, There was no significant difference in the number of broken (Type 2) USVs produced by WT versus Srcthl/thl females across time (n = 11 WT, n = 10 Srcthl/thl). E, There is a significant difference in the number of frequency modulated (Type 3) USVs produced by WT versus Srcthl/thl females at minutes 1 and 2 (n = 11 WT, n = 10 Srcthl/thl). Data are presented as mean ± SEM for each time point. *p < 0.05 between genotypes.
Mentions: Srcthl/thl and WT male mice emitted similar numbers of ultrasonic calls during the 5 min encounter with a female mouse. Repeated-measure ANOVA revealed no significant difference between groups across time (p = 0.4512) (Fig. 3A).

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