title: Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I
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.
authors.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.
authors.forename: Laleh
authors.initials: L
authors.lastname: Sinai
authors.affiliation: Programs in Genomics and Developmental Biology, The Hospital for Sick Children Research Institute, Peter Gilgan Center for Research and Learning , Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Evgueni A
authors.initials: EA
authors.lastname: Ivakine
authors.affiliation: Institute of Medical Science, University of Toronto , Toronto, Ontario, M5S 1A8, Canada.
authors.forename: Emily
authors.initials: E
authors.lastname: Lam
authors.affiliation: Department of Physiology, University of Toronto , Toronto, Ontario, M5S 1A8.
authors.forename: Marielle
authors.initials: M
authors.lastname: Deurloo
authors.affiliation: Department of Psychology, Center for Biological Timing and Cognition, University of Toronto , Toronto, Ontario, M5S 3G3, Canada.
authors.forename: Joana
authors.initials: J
authors.lastname: Dida
authors.affiliation: Department of Molecular Genetics, University of Toronto , Toronto, Ontario, M5S 1A8, Canada.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Zirngibl
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jung
authors.forename: Jane E
authors.initials: JE
authors.lastname: Aubin
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Feng
authors.forename: John
authors.initials: J
authors.lastname: Yeomans
authors.forename: Roderick R
authors.initials: RR
authors.lastname: McInnes
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Osborne
authors.forename: John C
authors.initials: JC
authors.lastname: Roder
keywords: Src tyrosine kinase; Williams-Beuren syndrome; calcium channel; general transcription factor 2 I; mouse behavior