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Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications

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  • Kota Tamada

    (RIKEN Brain Science Institute, Wako
    Hiroshima University, Minami
    Kobe University School of Medicine, Chuo)

  • Keita Fukumoto

    (RIKEN Brain Science Institute, Wako
    Hiroshima University, Minami)

  • Tsuyoshi Toya

    (RIKEN Brain Science Institute, Wako
    Keio University, Minato)

  • Nobuhiro Nakai

    (RIKEN Brain Science Institute, Wako
    Hiroshima University, Minami
    Kobe University School of Medicine, Chuo)

  • Janak R. Awasthi

    (RIKEN Brain Science Institute, Wako
    Saitama University, Sakura)

  • Shinji Tanaka

    (The University of Tokyo, Bunkyo)

  • Shigeo Okabe

    (The University of Tokyo, Bunkyo)

  • François Spitz

    (University of Chicago)

  • Fumihito Saitow

    (Garduate School of Medicine, Nippon Medical School, Bunkyo)

  • Hidenori Suzuki

    (Garduate School of Medicine, Nippon Medical School, Bunkyo)

  • Toru Takumi

    (RIKEN Brain Science Institute, Wako
    Hiroshima University, Minami
    Kobe University School of Medicine, Chuo
    Saitama University, Sakura)

Abstract

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.

Suggested Citation

  • Kota Tamada & Keita Fukumoto & Tsuyoshi Toya & Nobuhiro Nakai & Janak R. Awasthi & Shinji Tanaka & Shigeo Okabe & François Spitz & Fumihito Saitow & Hidenori Suzuki & Toru Takumi, 2021. "Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24359-3
    DOI: 10.1038/s41467-021-24359-3
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