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转录因子 2I 通过 TRPC3 调控 7q11.23 缺失综合征模型中的神经元发育。

Transcription Factor 2I Regulates Neuronal Development via TRPC3 in 7q11.23 Disorder Models.

机构信息

Department of Physiology, University of Toronto, 1 King's College Circle, 3306 Medical Sciences Building, Toronto, ON, M5S 1A8, Canada.

Department of Functional Genomics, CNCR, Neuroscience Campus Amsterdam, VU University and VU Medical Center, 1081 HV, Amsterdam, Netherlands.

出版信息

Mol Neurobiol. 2019 May;56(5):3313-3325. doi: 10.1007/s12035-018-1290-7. Epub 2018 Aug 17.

DOI:10.1007/s12035-018-1290-7
PMID:30120731
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6477017/
Abstract

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) had increased axonal outgrowth and increased TRPC3-mediated calcium entry upon carbachol stimulation. In contrast, mice with 3 copies of Gtf2i (Gtf2i) 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.

摘要

威廉姆斯综合征（WS）和 7q11.23 重复综合征（Dup7q11.23）是由染色体 7q11.23 上约 25 个蛋白编码基因的缺失和重复分别引起的神经发育障碍。一般转录因子 2I（GTF2I，蛋白 TFII-I）是这些蛋白之一，与 WS 和 Dup7q11.23 的神经发育表型有关。在这里，我们研究了 Gtf2i 拷贝数变化对神经元成熟和细胞内钙进入机制的影响，这些机制与该过程有关。只有一个 Gtf2i 拷贝的小鼠（Gtf2i）在 carbachol 刺激下具有增加的轴突生长和增加的 TRPC3 介导的钙进入。相比之下，有 3 个 Gtf2i 拷贝的小鼠（Gtf2i）的轴突生长和 TRPC3 介导的钙进入减少。潜在的机制是 TFII-I 不影响 TRPC3 蛋白表达，而是调节 TRPC3 膜易位。总之，我们的结果为 7q11.23 相关疾病背景下神经元成熟的细胞机制提供了新的功能见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/2c0be1b09da9/12035_2018_1290_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/a49d3b537f96/12035_2018_1290_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/3bc8a9057723/12035_2018_1290_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/f1d36e25578a/12035_2018_1290_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/20a4f1e31caa/12035_2018_1290_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/996cdb356965/12035_2018_1290_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/e9f79b5a3924/12035_2018_1290_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/2c0be1b09da9/12035_2018_1290_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/a49d3b537f96/12035_2018_1290_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/3bc8a9057723/12035_2018_1290_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/f1d36e25578a/12035_2018_1290_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/20a4f1e31caa/12035_2018_1290_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/996cdb356965/12035_2018_1290_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/e9f79b5a3924/12035_2018_1290_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2866/6477017/2c0be1b09da9/12035_2018_1290_Fig7_HTML.jpg

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