The Role And Mechanism Of Autism Risk Gene Chd8 In Neuron Proliferation And Differentiation

Autism spectrum disorder(ASD)is a widespread neurodevelopmental disorder.Studies have shown that genetic factors play an important role in the pathogenesis of ASD.However,its pathogenesis has not been fully defined and effective treatment methods and means are still lack.CHD8 is one of the high-risk genes for ASD discovered in recent years.A high proportion of patients with the mutation of CHD8 have been diagnosed with autism,and nearly 80% show the clinical symptom of macrocephaly.Our previous study found that knockout of the chd8 gene in zebrafish reproduces the phenotype of macrocephaly and autistic-like behavior similar to that in humans and mice,suggesting that the biological function of this gene is highly conserved.However,the mechanism by which CHD8 defects cause macrocephaly is still unclear.In this study,it was found that chd8 knockout or knockout could lead to the up-regulation of the expression of cell proliferation marker pcna in zebrafish embryos,and the expression of nestin and sox2 markers of nerve cell proliferation was also increased.At the same time,the expression of early and late markers of neuronal differentiation neurod1 and huc was down-regulated.These results indicate that chd8 defects lead to excessive proliferation of early neurons in zebrafish,while the number of neurons tending to differentiation decreases,suggesting that chd8 regulates the fate conversion and dynamic balance of early neuron proliferation and differentiation.Among the molecules that have been reported to be regulated by chd8,stat3 is involved in neuron proliferation and differentiation.In chd8 deficient bodies,the expression of stat3 was up-regulated and that of socs3 a,which is the negative feedback regulatory factor of stat3 in the downstream,was down.Drug inhibition of JAK-STAT signaling pathway can alleviate early hyperproliferation and normalize neural differentiation.It has been reported that the JAK-STAT pathway can crosstalk with Notch pathway,which plays an important role in neuron proliferation and differentiation.By detecting chd8 defects,it was found that the expression levels of key receptor genes notch1 a,notch1b,ligand gene delta A and downstream target gene her4.1 of Notch pathway were up-regulated,and Notch signal showed over-activation.However,inhibition of Notch signaling pathway can effectively save the phenotype of early abnormal neuron proliferation and differentiation.These results suggest that chd8 may affect the proliferation and differentiation of early nerve cells by regulating the expression of some key factors in the Notch and JAK-STAT signaling pathways,and suggest that the abnormality of early neurogenesis may be one of the important causes of macrocephaly in autism patients.