Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications.
Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications.
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DOI：
10.1038/s41467-021-24359-3
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发表时间：
2021-07-01
影响因子：
16.6
通讯作者：
Takumi T
中科院分区：
文献类型：
--
作者：
Tamada K;Fukumoto K;Toya T;Nakai N;Awasthi JR;Tanaka S;Okabe S;Spitz F;Saitow F;Suzuki H;Takumi T
母系遗传性染色体15 q11-q13重复（Dup 15 q）是一种与自闭症谱系障碍（ASD）相关的致病性拷贝数变异（CNV）。最近，父源性重复也被证明有助于ASD的发展。父系Dup 15 q的分子机制尚不清楚。在这里，我们进行遗传和过表达为基础的筛选，并确定Necdin（Ndn）作为一个驱动基因的父系Dup 15 q导致在小鼠中的ASD样表型的发展。过量的Ndn导致增强的棘形成和密度以及皮质锥体神经元的过度兴奋。我们通过使用CRISPR-Cas9系统从Dup 15 q小鼠中切除其一个拷贝来产生具有归一化拷贝数的Ndn的15 q dupΔNdn小鼠。15 q dupΔNdn小鼠没有表现出ASD样表型，并且表现出与野生型动物相似的树突棘动力学和皮质兴奋-抑制平衡。我们的研究提供了一个深入了解Ndn在父亲15 q重复和父亲Dup 15 q综合征的小鼠模型中的作用。染色体15 q11-q13的重复与自闭症谱系障碍（ASD）有关。在这里，作者表明，在小鼠中，父本Dup 15 q导致由Necdin驱动的ASD样神经元和行为障碍。
Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome. Duplication of chromosome 15q11-q13 is associated with autism spectrum disorder (ASD). Here, the authors show that in mice paternal Dup15q results in ASD-like neuronal and behavioural impairment driven by Necdin.
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