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A human neurodevelopmental model for Williams syndrome

机译：威廉姆斯综合征的人类神经发育模型

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摘要

Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome(6,7), we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of postmortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells(8) fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.
机译：威廉姆斯综合征是一种遗传性神经发育障碍，其特征是罕见的超社交能力以及保留和受损的语言和认知能力的结合体。几乎所有临床诊断出的威廉姆斯综合征患者都缺乏完全相同的基因集，其染色体带位于7q11.23染色体断裂点（参考文献1-5）。特定基因对神经解剖学和功能改变的贡献，导致人类的行为病理学，在很大程度上尚待探索。在这里，我们研究了源自威廉姆斯综合征的神经祖细胞和皮质神经元，它们通常发育为诱导性多能干细胞。与通常发育的神经祖细胞相比，威廉姆斯综合征中的神经祖细胞具有增加的倍增时间和凋亡。使用具有非典型威廉姆斯综合征的个体（6,7），我们将该细胞表型缩小为单个基因候选者，卷曲的9（FZD9）。在神经元阶段，源自Williams综合征的V / VI层皮质神经元的特征是更长的总树突，增加的刺和突触数量，异常的钙振荡和改变的网络连通性。在死后V / VI层皮层神经元进行高尔基染色后，验证了Williams综合征神经元中观察到的形态学变化。这种人类诱导的多能干细胞模型（8）填补了Williams综合征细胞生物学目前的知识空白，并可能导致对该疾病和人类社交脑的分子机制的进一步了解。

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  • 来源
    《Nature》 |2016年第7616期|338-343|共6页
  • 作者

    Chailangkarn Thanathom; Trujillo Cleber A.; Freitas Beatriz C.; Hrvoj-Mihic Branka; Herai Roberto H.; Yu Diana N.; Brown Timothy T.; Marchetto Maria C.; Bardy Cedric; McHenry Lauren; Stefanacci Lisa; Jarvinen Anna; Searcy Yvonne M.; DeWitt Michelle; Wong Wenny; Lai Philip; Ard M. Colin; Hanson Kari L.; Romero Sarah; Jacobs Bob; Dale Anders M.; Dai Li; Korenberg Julie R.; Gage Fred H.; Bellugi Ursula; Halgren Eric; Semendeferi Katerina; Muotri Alysson R.;

  • 作者单位

    Univ Calif San Diego, Sch Med, UCSD Stem Cell Program, Dept Pediat,Rady Childrens Hosp San Diego, La Jolla, CA 92037 USA|Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92037 USA|CARTA, La Jolla, CA 92093 USA|Natl Ctr Genet Engn & Biotechnol BIOTEC, Virol & Cell Technol Lab, Pathum Thani 12120, Thailand;

    Univ Calif San Diego, Sch Med, UCSD Stem Cell Program, Dept Pediat,Rady Childrens Hosp San Diego, La Jolla, CA 92037 USA|Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92037 USA|CARTA, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Sch Med, UCSD Stem Cell Program, Dept Pediat,Rady Childrens Hosp San Diego, La Jolla, CA 92037 USA|Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92037 USA|CARTA, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Dept Anthropol, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Sch Med, UCSD Stem Cell Program, Dept Pediat,Rady Childrens Hosp San Diego, La Jolla, CA 92037 USA|Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92037 USA|CARTA, La Jolla, CA 92093 USA|Pontificia Univ Catolica Parana PUCPR, Grad Program Hlth Sci, Sch Med, Curitiba, Parana, Brazil;

    Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;

    Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA|Univ Calif San Diego, Ctr Human Dev, La Jolla, CA 92093 USA;

    Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;

    Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA|Flinders Univ S Australia, SAHMRI Mind & Brain Theme, Sch Med, Lab Human Neurophysiol & Genet, Adelaide, SA 5000, Australia;

    Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;

    Univ Calif San Diego, Sch Med, UCSD Stem Cell Program, Dept Pediat,Rady Childrens Hosp San Diego, La Jolla, CA 92037 USA|Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92037 USA|CARTA, La Jolla, CA 92093 USA|Univ Calif San Diego, Dept Anthropol, La Jolla, CA 92093 USA;

    Salk Inst Biol Studies, Lab Cognit Neurosci, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;

    Salk Inst Biol Studies, Lab Cognit Neurosci, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;

    Salk Inst Biol Studies, Lab Cognit Neurosci, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;

    Salk Inst Biol Studies, Lab Cognit Neurosci, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;

    Salk Inst Biol Studies, Lab Cognit Neurosci, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;

    Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Dept Anthropol, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Sch Med, UCSD Stem Cell Program, Dept Pediat,Rady Childrens Hosp San Diego, La Jolla, CA 92037 USA|Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92037 USA|CARTA, La Jolla, CA 92093 USA;

    Colorado Coll, Dept Psychol, Colorado Springs, CO 80903 USA;

    Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Radiol, La Jolla, CA 92093 USA|Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA;

    Univ Utah, Dept Pediat, Salt Lake City, UT 84108 USA|Univ Utah, Inst Brain, Salt Lake City, UT 84108 USA;

    Univ Utah, Dept Pediat, Salt Lake City, UT 84108 USA|Univ Utah, Inst Brain, Salt Lake City, UT 84108 USA;

    Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA|Univ Calif San Diego, Kavli Inst Brain & Mind, La Jolla, CA 92093 USA;

    Salk Inst Biol Studies, Lab Cognit Neurosci, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;

    Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA|Univ Calif San Diego, Kavli Inst Brain & Mind, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Dept Anthropol, La Jolla, CA 92093 USA|Univ Calif San Diego, Kavli Inst Brain & Mind, La Jolla, CA 92093 USA|Univ Calif San Diego, Neurosci Grad Program, Sch Med, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Sch Med, UCSD Stem Cell Program, Dept Pediat,Rady Childrens Hosp San Diego, La Jolla, CA 92037 USA|Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92037 USA|CARTA, La Jolla, CA 92093 USA|Univ Calif San Diego, Kavli Inst Brain & Mind, La Jolla, CA 92093 USA|Univ Calif San Diego, Neurosci Grad Program, Sch Med, La Jolla, CA 92093 USA;

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