期刊
NEUROSCIENCE BULLETIN
卷 39, 期 9, 页码 1333-1347出版社
SPRINGER
DOI: 10.1007/s12264-022-00997-5
关键词
WDR62; Microcephaly; Autism spectrum disorder; Synapse; Retinoic acid
The study reveals a correlation between abnormal brain size and increased frequency of autism spectrum disorder (ASD) in offspring, with heterozygous mutations of the WDR62 gene associated with ASD. Knockout of Wdr62 in mice leads to reduced brain size and impaired learning/memory, as well as ASD-like behaviors. However, depletion of WDR62 specifically in differentiated neurons results in largely normal brain size but aberrant social interactions and repetitive behaviors, indicating a complex role for WDR62 in ASD etiology.
Brain size abnormality is correlated with an increased frequency of autism spectrum disorder (ASD) in offspring. Genetic analysis indicates that heterozygous mutations of the WD repeat domain 62 (WDR62) are associated with ASD. However, biological evidence is still lacking. Our study showed that Wdr62 knockout (KO) led to reduced brain size with impaired learning and memory, as well as ASD-like behaviors in mice. Interestingly, Wdr62 Nex-cKO mice (depletion of WDR62 in differentiated neurons) had a largely normal brain size but with aberrant social interactions and repetitive behaviors. WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. Finally, we revealed that retinoic acid gavages significantly alleviated ASD-like behaviors in mice with WDR62 haploinsufficiency, probably by complementing the expression of ASD and synapse-related genes. Our findings provide a new perspective on the relationship between the microcephaly gene WDR62 and ASD etiology that will benefit clinical diagnosis and intervention of ASD.
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