The Role Of NRG1/ErbB4 Signaling In Abnormal Behavior Of MeCP2-deficient Mice

Rett syndrome(RTT syndrome)is a genetic disease associated with X chromosome which occurs in female patients with the incidence of 1/10000.Rett syndrome patients often manifestate brain developmental delay,stereotyped movements,breathing disorders,movement disorders,and autism-like social disorder,along with higher risk of epilepsy when getting older.MeCP2 is a pathogenicity gene of Rett syndrome,which is located on the Xq28 region of the X chromosome.MeCP2 encodes a methylated CpG-binding protein MeCP2,which is a transcriptional regulator that regulates gene transcription,RNA splicing as well as miRNA expression.MeCP2 deletion or insertion of loxp sequence may cause behavioral abnormalities in mice,suggesting that further studies of MeCP2-deficient correlations such as MeCP2lox/y and MeCP2stop/y mice may be wanted.NRG1 is a neuro-regulatory growth factor belonging to the NRG family together with three other homologous proteins NRG2,NRG3 and NRG4.NRG1 is mainly expressed on the synapse and glia cells in the brain.It regulates the expression of neuronal receptors and plays an important role in synaptic plasticity,neuron migration,and neuron growth and development.NRG1 plays an important role in neuronal cell proliferation,apoptosis,migration,and differentiation through the binding with ErbB4,a receptor tyrosine-kinase ErbB family.Abnormal NRG1/ErbB4 signal pathways lead to a number of neurological diseases such as schizophrenia,epilepsy,and autism..In the previous work,we detected abnormal PPI in MeCP21ox/y mice,whereas diseases associated with PPI,such as schizophrenia,showed an abnormal NRG 1/ErbB4 signaling pathway.To investigate whether MeCP2-related disease abnormality is associated with NRG1/ErbB4 signaling pathway,we examined the expression of NRG1 and ErbB4 in MeCP2 mutant mice,the results showed that NRG1 in cortex and hippocampus were significantly lower in the mutants,and ErbB4 is only overexpressed in the hippocampus but not in the cortex.These results suggest that abnormal behavior caused by MeCP2 defects in mice may be associated with the NRG1/ErbB4 signaling pathway.noteworthyly,we found that some of the behavioral effects of NRG1 were improved after exogenous injection of NRG1.It confirms that NRG1 may be an effective target for diseases caused by MeCP2 deficiency.Our research will bring more research ideas to the disease related to MeCP2 gene defect and provide a possible therapeutic basis in clinical treatment.