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Kctd13 deletion reduces synaptic transmission via increased RhoA

机译：Kctd13删除通过增加RhoA减少突触传递

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摘要

Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders(1-6) and are among the most prevalent in autism spectrum disorders(1,2,7). Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes(8,9). The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study(8), deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.
机译：16号染色体区域16p11.2的拷贝数变异与神经精神疾病有关（1-6），是自闭症谱系障碍中最普遍的疾病（1,2,7）。在许多16p11.2基因中，Kctd13被认为是神经发育表型的主要驱动力（8,9）。然而，KCTD13在哺乳动物脑中的功能仍然未知。在这里，我们删除小鼠中的Kctd13基因，并证明突触传递减少。突触传递的减少与Ras同源基因家族A（RhoA），KCTD13 / CUL3泛素连接酶底物水平的升高有关，并且被RhoA抑制所逆转，提示RhoA升高是重要的机制。与先前的敲低研究相反（8），删除Kctd13或kctd13不会分别增加小鼠或斑马鱼的大脑大小或神经发生。这些发现暗示了Kctd13在与神经精神疾病有关的神经元功能的调节中，并阐明了Kctd13在神经发生和大脑大小中的作用。我们的数据还揭示了RhoA作为与KCTD13缺失相关的疾病的治疗靶标的潜在作用。

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  • 来源
    《Nature》 |2017年第7679期|227-231|共5页
  • 作者

    Escamilla Christine Ochoa; Filonova Irina; Walker Angela K.; Xuan Zhong X.; Holehonnur Roopashri; Espinosa Felipe; Liu Shunan; Thyme Summer B.; Lopez-Garcia Isabel A.; Mendoza Dorian B.; Usui Noriyoshi; Ellegood Jacob; Eisch Amelia J.; Konopka Genevieve; Lerch Jason P.; Schier Alexander F.; Speed Haley E.; Powell Craig M.;

  • 作者单位

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA|Grad Univ, Okinawa Inst Sci & Technol, Fac Affairs Off, 1919-1 Tancha, Onna Son, Okinawa 9040495, Japan;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA;

    Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA|Univ Fukui, Res Ctr Child Mental Dev, Div Dev Mental Funct, Fukui 9101193, Japan|Chiba Univ, United Grad Sch Child Dev, Hamamatsu Univ,Kanazawa Univ,Osaka Univ, Div Dev Higher Brain Funct,Sch Med, Osaka 5650871, Japan|Univ Fukui, Osaka 5650871, Japan;

    Hosp Sick Children, Mouse Imaging Ctr MICe, Toronto, ON M5T 3H7, Canada;

    Univ Texas Southwestern Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA|Univ Penn, Perelman Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA|Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA;

    Hosp Sick Children, Mouse Imaging Ctr MICe, Toronto, ON M5T 3H7, Canada|Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1X8, Canada;

    Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA|Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA|Broad Inst MIT & Harvard, Cambridge, MA 02142 USA|Harvard Stem Cell Inst, Cambridge, MA 02138 USA|Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA;

    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA|Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA|Univ Texas Southwestern Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA;

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