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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

Craniofacial dysmorphology and growth retardation in Srcthl/thl mice. A, Whole genome scan in (S129 x C57BL/6) F2 toothless mice demonstrated linkage to D2Mit411. Additional markers were used to refine the critical interval (highlighted in yellow). S, Homozygous for S129 allele; H, heterozygous for S129 and C57BL6 alleles; NT, not tested. B, Mutant mice have insertion of a C nucleotide in exon 12 of the Src gene. C, No Src protein was detected in immunoblot of whole-brain lysates from Srcthl/thl mice. D, Faxitron images of WT and Srcthl/thl mouse skulls in lateral (L) and superior (S) views with landmarks used for cephalometric analysis indicated and described in Materials and Methods. Abbreviations are defined in Table 1’s footnote. Analysis of the data is summarized in Table 1. E, Weight of WT and Srcthl/thl mice shown as mean ± SEM (n = 10 WT, n = 9 Srcthl/thl).
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Figure 1: Craniofacial dysmorphology and growth retardation in Srcthl/thl mice. A, Whole genome scan in (S129 x C57BL/6) F2 toothless mice demonstrated linkage to D2Mit411. Additional markers were used to refine the critical interval (highlighted in yellow). S, Homozygous for S129 allele; H, heterozygous for S129 and C57BL6 alleles; NT, not tested. B, Mutant mice have insertion of a C nucleotide in exon 12 of the Src gene. C, No Src protein was detected in immunoblot of whole-brain lysates from Srcthl/thl mice. D, Faxitron images of WT and Srcthl/thl mouse skulls in lateral (L) and superior (S) views with landmarks used for cephalometric analysis indicated and described in Materials and Methods. Abbreviations are defined in Table 1’s footnote. Analysis of the data is summarized in Table 1. E, Weight of WT and Srcthl/thl mice shown as mean ± SEM (n = 10 WT, n = 9 Srcthl/thl).

Mentions: Genome-wide mapping studies were performed on 20 affected mice using a panel of microsatellite markers positioned approximately 20 cM apart. For narrowing down the critical interval, both microsatellite and single nucleotide polymorphism markers were used. All markers and their corresponding positions, according to the Ensembl database, are listed in Figure 1A. Genotyping was performed at The Center for Applied Genomics, Toronto. After placing the Src gene within the critical interval, we sequenced the Src coding region from one affected mouse and confirmed the Srcthl mutation.


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)

Craniofacial dysmorphology and growth retardation in Srcthl/thl mice. A, Whole genome scan in (S129 x C57BL/6) F2 toothless mice demonstrated linkage to D2Mit411. Additional markers were used to refine the critical interval (highlighted in yellow). S, Homozygous for S129 allele; H, heterozygous for S129 and C57BL6 alleles; NT, not tested. B, Mutant mice have insertion of a C nucleotide in exon 12 of the Src gene. C, No Src protein was detected in immunoblot of whole-brain lysates from Srcthl/thl mice. D, Faxitron images of WT and Srcthl/thl mouse skulls in lateral (L) and superior (S) views with landmarks used for cephalometric analysis indicated and described in Materials and Methods. Abbreviations are defined in Table 1’s footnote. Analysis of the data is summarized in Table 1. E, Weight of WT and Srcthl/thl mice shown as mean ± SEM (n = 10 WT, n = 9 Srcthl/thl).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Craniofacial dysmorphology and growth retardation in Srcthl/thl mice. A, Whole genome scan in (S129 x C57BL/6) F2 toothless mice demonstrated linkage to D2Mit411. Additional markers were used to refine the critical interval (highlighted in yellow). S, Homozygous for S129 allele; H, heterozygous for S129 and C57BL6 alleles; NT, not tested. B, Mutant mice have insertion of a C nucleotide in exon 12 of the Src gene. C, No Src protein was detected in immunoblot of whole-brain lysates from Srcthl/thl mice. D, Faxitron images of WT and Srcthl/thl mouse skulls in lateral (L) and superior (S) views with landmarks used for cephalometric analysis indicated and described in Materials and Methods. Abbreviations are defined in Table 1’s footnote. Analysis of the data is summarized in Table 1. E, Weight of WT and Srcthl/thl mice shown as mean ± SEM (n = 10 WT, n = 9 Srcthl/thl).
Mentions: Genome-wide mapping studies were performed on 20 affected mice using a panel of microsatellite markers positioned approximately 20 cM apart. For narrowing down the critical interval, both microsatellite and single nucleotide polymorphism markers were used. All markers and their corresponding positions, according to the Ensembl database, are listed in Figure 1A. Genotyping was performed at The Center for Applied Genomics, Toronto. After placing the Src gene within the critical interval, we sequenced the Src coding region from one affected mouse and confirmed the Srcthl mutation.

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