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Chinese Researchers Report for the First-time Neurodevelopmental Abnormality in a Non-human Primate Carrying a SHANK3 Mutation
Autism is a common neurodevelopmental disorder characterized by impaired social communication, restricted and repetitive behavior or interests. The reported prevalence for autism has been rising world-wide. Due to the application of large-scale exome sequencing in recent years, hundreds of novel autism associated genes have been identified. Mutations in SHANK3 remain one of the best characterized and replicated genetic defects in autism in humans. Genetically modified Shank3 mutant mice have served as valuable tools to dissect the pathophysiology of SHANK3 causing autism. However, the significant evolutional differences between mouse and human brain and behaviors pose many challenges to assess the translational value of the mouse models to humans and highlight the demand of developing non-human primate models.
Recently, the researchers from Dr. ZHANG Yongqing’s group at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences (CAS), found neurodevelopmental abnormality in SHANK3-deficient non-human primate for the first time.
Using the CRISPR/Cas9 to target the SHANK3 gene in the embryos of cynomolgus monkeys, the researchers successfully generated three mutant monkey offspring with various deleterious mutations in the SHANK3 gene. They analyzed the targeted mutations in various tissues from the three animals, as well as various brain regions of the deceased animals by immunochemical analysis. SHANK3 complete deficiency resulted in a significant reduction in postsynaptic proteins such as GluN2B, PSD95, mGluR5 and increased cytosolic localization of Homer1b/c. The number of mature neurons was markedly reduced but activated astrocytes were increased in the prefrontal cortex in SHANK3 brain. The neuropathology caused by the complete loss of SHANK3 in monkey brain is remarkably distinct from the findings reported from Shank3 knockout mice.
These findings indicate that SHANK3 is essential for the early development of primate brains. The novel role of SHANK3 in early brain development is critical to the autism field.
This work is a product of substantial collaboration between teams led by Drs. LI Xiaojiang (CAS), JIANG Yonghui (Duke University Medical Center), LU Youming (Huazhong University of Science and Technology), and Yuanxi Biotech Inc. Guangzhou. The work entitled “Altered neurogenesis and disrupted expression of synaptic proteins in prefrontal cortex of SHANK3-deficient non-human primate” has been advance online published in Cell Research (doi:10.1038/cr.2017.95).
The project was supported by the Ministry of Science and Technology of China, the Chinese Academy of Sciences, and the National Natural Science Foundation of China.
Dr. ZHANG Yongqing