Hongyan Wang

Speaker: Hongyan Wang

Title: MeCP2 in Autism – Displays Allelic Expression Imbalance and Affects both Nerve System and Heart Development Through Notch Pathway


Both Autism and Rett syndrome are neural development disorders sharing certain characterizations such as impaired social interaction or communication, and the restricted and repetitive behavior. However, they have very different sexual bias as autism affects 4-5 boys versus 1 girl while Rett syndrome mainly affects girls with limited boys. Mutations of MeCP2 (Methyl-CpG-binding protein 2), an l X chromosome gene, has been identified not only in most Rett syndrome patients, but also in autism patients. To understand whether MeCP2 contributes to the sexual imbalance in autism, we analyzed the expression of MeCP2 in both Rhesus monkey (Macaca mulatta) and mouse. Interestingly, we found that the expression of MeCP2 in brain did not follow XCI (X chromosome inactivation) in both species. By using C57B/L6 MeCP2S80A transgenic mouse crossed with FVB WT mouse, allelic expression imbalance (AEI) of MeCP2 in brain was observed when the mutation is from the maternal side but not from the paternal side. This might significantly reduce the chance of female offsprings’ abnormality due to MeCP2 mutations even in consideration of X chromosome compensation, which in turn contributes to the sexual bias effects in autism. To further study the functions of MeCP2 in autism, we sequenced 288 autism patients and 383 controls. Five rare nonsynonymous mutations (T197M, G232A, H371R, E392K, G426S) were individually identified in autism patients of four boys and one girl. Functional analysis in zebrafish showed that those mutations lose the ability to rescue the abnormal defects in both brain and heart caused by MeCP2 morpholinos injection. However, when overexpressed, those mutations caused more severe defects compared to WT MeCP2. By using human U251 cells, we found that WT MeCP2 could inhibit the Notch signaling by down-regulating ADAM10 expression whereas those autistic mutants lost the inhibition variably. Most importantly, it was found that the possible underlying molecular mechanism is due to WT MeCP2, not the mutated MeCP2, up-regulating the expression of mir-197, a strong inhibitor on ADAM10 mRNA level. Such loss-of-function MeCP2 mutations on ADAM10/Notch regulation further contribute to defective brain and heart as what we have observed in zebrafish since Notch signaling is very important for both organs development.