The Establishment Of Autism Risk Gene CUL3 Mutant Zebrafish And Behavioral Studies

Autism is heterogeneous class of neurodevelopmental disorders(autism spectrum disorder,ASD)with a high degree of heritability.At present,there is a lack of biological diagnosis and effective treatment.The whole genome association analysis shows that the defects of CULLIN3(CUL3)gene are highly correlated with ASD.Cul3 mutant mice showed autism like behavior,indicating conservation between species.However,the role of CUL3 in the development of nervous system is largely unknown and particularly,it is still mysterious about how its mutations cause autism.Zebrafish is a widely used model animal in recent years,which has unique advantages in the research of neurodevelopmental mechanisms of-related neuropsychiatric diseases.We knocked out Cul3 gene in zebrafish by CRISPR/cas9 technology and obtained three Cul3 mutants.In this study,we selected a Cul3 mutant with 10 bases missing.We tested the behavior of Cul3 mutant.The experiments of open field,social preference,mirror image and shoaling showed that the mutant had social defects and many behavioral abnormalities.Social impairment is closely related to the expression of c-Fos and Crh(coriotropin releasing hormone).The transcription level of c-Fos and Crh in Cul3a-/-zebrafish showe a significant upregulation and downregulation respectively,indicating that the brain of Cul3a-/-zebrafish may be in an over activated state,while the expression of the neuron marker gene HuC is also significantly reduced.Besides,eIF4G microexons are also associated with social impairment,and the transcriptional levels of eIF4G1a and eIF4G3a in Cul3a-/-zebrafia are significantly reduced The changes of the above molecular level might be correlated with the behavioral phenotypes of the mutants.Zebrafish,as an ideal animal model for neurodevelopmental research and drug screening,will help us to further understand the function of CUL3 in the nervous system and the pathology of ASD.