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

• Published in: Nature communications 2021-07, Vol.12 (1), p.4056-4056, Article 4056
• Main Authors: Tamada, Kota, Fukumoto, Keita, Toya, Tsuyoshi, Nakai, Nobuhiro, Awasthi, Janak R., Tanaka, Shinji, Okabe, Shigeo, Spitz, François, Saitow, Fumihito, Suzuki, Hidenori, Takumi, Toru
• Format: Article
• Language: English
• Subjects: 13/51; 14; 14/69; 38; 38/77; 42; 45; 45/88; 49; 59; 631/378/1689/1373; 631/378/2583; 631/378/340; 64; 64/60; 96; Animals; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autism Spectrum Disorder - pathology; Behavior, Animal - physiology; Chromosome 15; Chromosomes; Chromosomes, Human, Pair 15 - genetics; Copy number; CRISPR; Dendritic spines; Disease Models, Animal; Female; Gene duplication; Humanities and Social Sciences; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; multidisciplinary; Necdin; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurogenesis; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotype; Phenotypes; Pyramidal cells; Reproduction (copying); Science; Science (multidisciplinary); Spine; Trisomy - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24359-3

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.