PT - JOURNAL ARTICLE AU - Laleh Sinai AU - Evgueni A. Ivakine AU - Emily Lam AU - Marielle Deurloo AU - Joana Dida AU - Ralph A. Zirngibl AU - Cynthia Jung AU - Jane E. Aubin AU - Zhong-Ping Feng AU - John Yeomans AU - Roderick R. McInnes AU - Lucy R. Osborne AU - John C. Roder TI - Disruption of Src is associated with phenotypes related to Williams-Beuren syndrome and altered cellular localization of TFII-I AID - 10.1523/ENEURO.0016-14.2015 DP - 2015 Mar 06 TA - eneuro PG - ENEURO.0016-14.2015 4099 - http://www.eneuro.org/content/early/2015/03/06/ENEURO.0016-14.2015.short 4100 - http://www.eneuro.org/content/early/2015/03/06/ENEURO.0016-14.2015.full AB - Src is a non-receptor 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 hyper-sociability 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 behavioural phenotypes observed in WBS through its regulation of TFII-I. Significance Statement: Src tyrosine kinase phosphorylates the general transcription factor protein TFII-I, which is deleted in the neurodevelopmental disorder Williams-Beuren syndrome (WBS). We identified phenotypes such as increased sociability, visuospatial deficits, craniofacial abnormalities and hyperactivity that overlap with symptoms of WBS, in a mouse with disruption of Src. We also demonstrated altered cellular localization of TFII-I and of the TRPC3 calcium channel subunit, which is regulated by TFII-I. The finding that the Src null mouse phenocopies some features of WBS confirms its crucial role in the development and function of the nervous system, possibly through mediating changes in the cellular localization and function of TRPC3, and leading to altered agonist-induced calcium entry.