Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I

Laleh Sinai; Evgueni A Ivakine; Emily Lam; Marielle Deurloo; Joana Dida; Ralph A Zirngibl; Cynthia Jung; Jane E Aubin; Zhong-Ping Feng; John Yeomans; Roderick R McInnes; Lucy R Osborne; John C Roder

doi:10.1523/ENEURO.0016-14.2015

Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I

eNeuro. 2015 Mar 30;2(2):ENEURO.0016-14.2015. doi: 10.1523/ENEURO.0016-14.2015. eCollection 2015 Mar-Apr.

Authors

Laleh Sinai¹, Evgueni A Ivakine², Emily Lam³, Marielle Deurloo⁴, Joana Dida⁵, Ralph A Zirngibl⁶, Cynthia Jung, Jane E Aubin, Zhong-Ping Feng, John Yeomans, Roderick R McInnes, Lucy R Osborne, John C Roder

Affiliations

¹ Institute of Medical Science, University of Toronto , Toronto, Ontario, M5S 1A8, Canada ; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto Ontario, M5S 3E1, Canada.
² 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.
³ Institute of Medical Science, University of Toronto , Toronto, Ontario, M5S 1A8, Canada.
⁴ Department of Physiology, University of Toronto , Toronto, Ontario, M5S 1A8.
⁵ Department of Psychology, Center for Biological Timing and Cognition, University of Toronto , Toronto, Ontario, M5S 3G3, Canada.
⁶ Department of Molecular Genetics, University of Toronto , Toronto, Ontario, M5S 1A8, 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.

Keywords: Src tyrosine kinase; Williams-Beuren syndrome; calcium channel; general transcription factor 2 I; mouse behavior.