TY - JOUR
T1 - Transcription Factor 2I Regulates Neuronal Development via TRPC3 in 7q11.23 Disorder Models
AU - Deurloo, Marielle H.S.
AU - Turlova, Ekaterina
AU - Chen, Wen Liang
AU - Lin, You Wei
AU - Tam, Elaine
AU - Tassew, Nardos G.
AU - Wu, Michael
AU - Huang, Ya Chi
AU - Crawley, Jacqueline N.
AU - Monnier, Philippe P.
AU - Groffen, Alexander J.A.
AU - Sun, Hong Shuo
AU - Osborne, Lucy R.
AU - Feng, Zhong Ping
N1 - Funding Information: Funding Information This work was funded by the following grants: Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants to Z.P.F. (RGPIN-2014-06471) and to H.S.S. (RGPIN-2016-04574), a Simons Foundation Autism Research Initiative Award to L.R.O. and J.N.C. (238896), and a Canadian Institutes of Health Research (CIHR) Operating Grant to L.R.O. and Z.P.F. (MOP77720). Publisher Copyright: © 2018, The Author(s).
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Williams syndrome (WS) and 7q11.23 duplication syndrome (Dup7q11.23) are neurodevelopmental disorders caused by the deletion and duplication, respectively, of ~ 25 protein-coding genes on chromosome 7q11.23. The general transcription factor 2I (GTF2I, protein TFII-I) is one of these proteins and has been implicated in the neurodevelopmental phenotypes of WS and Dup7q11.23. Here, we investigated the effect of copy number alterations in Gtf2i on neuronal maturation and intracellular calcium entry mechanisms known to be associated with this process. Mice with a single copy of Gtf2i (Gtf2i +/Del ) had increased axonal outgrowth and increased TRPC3-mediated calcium entry upon carbachol stimulation. In contrast, mice with 3 copies of Gtf2i (Gtf2i +/Dup ) had decreases in axon outgrowth and in TRPC3-mediated calcium entry. The underlying mechanism was that TFII-I did not affect TRPC3 protein expression, while it regulated TRPC3 membrane translocation. Together, our results provide novel functional insight into the cellular mechanisms that underlie neuronal maturation in the context of the 7q11.23 disorders.
AB - Williams syndrome (WS) and 7q11.23 duplication syndrome (Dup7q11.23) are neurodevelopmental disorders caused by the deletion and duplication, respectively, of ~ 25 protein-coding genes on chromosome 7q11.23. The general transcription factor 2I (GTF2I, protein TFII-I) is one of these proteins and has been implicated in the neurodevelopmental phenotypes of WS and Dup7q11.23. Here, we investigated the effect of copy number alterations in Gtf2i on neuronal maturation and intracellular calcium entry mechanisms known to be associated with this process. Mice with a single copy of Gtf2i (Gtf2i +/Del ) had increased axonal outgrowth and increased TRPC3-mediated calcium entry upon carbachol stimulation. In contrast, mice with 3 copies of Gtf2i (Gtf2i +/Dup ) had decreases in axon outgrowth and in TRPC3-mediated calcium entry. The underlying mechanism was that TFII-I did not affect TRPC3 protein expression, while it regulated TRPC3 membrane translocation. Together, our results provide novel functional insight into the cellular mechanisms that underlie neuronal maturation in the context of the 7q11.23 disorders.
KW - Animals
KW - Axons/metabolism
KW - Calcium/metabolism
KW - Cell Membrane/metabolism
KW - Chromosome Aberrations
KW - Cortical neurons
KW - Disease Models, Animal
KW - General transcription factor 2i
KW - Mice
KW - Neurites/metabolism
KW - Neurons/metabolism
KW - Phenotype
KW - TRPC Cation Channels/metabolism
KW - TRPC3
KW - Time Factors
KW - Transcription Factors, TFII/metabolism
KW - Williams-Beuren syndrome (WBS)
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U2 - https://doi.org/10.1007/s12035-018-1290-7
DO - https://doi.org/10.1007/s12035-018-1290-7
M3 - Article
C2 - 30120731
SN - 0893-7648
VL - 56
SP - 3313
EP - 3325
JO - Molecular neurobiology
JF - Molecular neurobiology
IS - 5
ER -