Abstract
Duplication of MECP2 (Methyl-CpG-binding protein 2) causes severe mental illness called MECP2 duplication syndrome (MDS), yet the underlying mechanism remains elusive. Here we show, in Tg(MECP2) transgenic mouse brain or cultured neural progenitor cells (NPCs), that elevated MeCP2 expression promotes NPC differentiation into neurons. Ectopic expression of MeCP2 inhibits ADAM10 and thus the NOTCH pathway during NPC differentiation. In human cells, this downregulation on ADAM10 was mediated by miRNA-197, which is upregulated by MeCP2. Surprisingly, miR-197 binds to the ADAM10 3′-UTR via its 3′ side, not the canonical seed sequence on the 5′ side. In mouse cells, a noncoding RNA Gm28836 is used to replace the function of miR-197 between MeCP2 and ADAM10. Similar to MeCP2, overexpressing miR-197 also promotes NPCs differentiation into neurons. Interestingly, three rare missense mutations (H371R, E394K, and G428S) in MECP2, which we identified in a Han Chinese autism spectrum disorders (ASD) cohort showed loss-of-function effects in NPC differentiation assay. These mutations cannot upregulate miR-197. Overexpressing miR-197 together with these MeCP2 mutations could rescue the downregulation on ADAM10. Not only the inhibitor of miR-197 could reverse the effect of overexpressed MeCP2 on NPCs differentiation, but also overexpression of miR-197 could reverse the NPCs differentiation defects caused by MECP2 mutations. Our results revealed that a regulatory axis involving MeCP2, miR-197, ADAM10, and NOTCH signaling is critical for NPC differentiation, which is affected by both MeCP2 duplication and mutation.
Highlights
MECP2, an X-linked gene encoding the methyl-cytosine binding protein MeCP2, is associated with two severe neurological disorders, RettThese authors contributed : Yu-Meng Wang, Yu-Fang ZhengEdited by L
To determine the effect of MECP2 duplication on cell fate in vivo in fetal brain, we investigated a Tg(MECP2) mouse line which had previously been used as a model for MECP2 duplication syndrome (MDS), as it contains an extra copy of human MECP2 and exhibits approximately doubled MeCP2 levels in the brain [33]
The results demonstrate that elevated MeCP2 expression affects neural progenitor cells (NPCs) cell fate and promotes neurogenesis
Summary
MECP2 (methyl-CpG binding protein 2), an X-linked gene encoding the methyl-cytosine binding protein MeCP2, is associated with two severe neurological disorders, Rett. MeCP2 was originally identified as a transcriptional repressor [7, 8], but recent studies have shown it has diverse functions, including transcription activation [9], mRNA splicing [10, 11], and microRNA (miRNA) processing [12, 13], to name but a few As both RTT and ASD patients show symptoms shortly after birth, most functional studies of MeCP2 have been focused on postnatal events such as dendritic arborization [14,15,16], synapse formation and plasticity [16,17,18], and adult neurogenesis [19,20,21]. We identified three rare missense MECP2 mutations (H371R, E394K, and G428S) in ASD patients in our Han Chinese ASD cohort, which are novel in the East Asian population according to ExAC [32] These MECP2 mutations resulted in dysfunctional regulation of miR-197 and neurogenesis. Our results revealed a novel regulatory pathway via miR-197 by which MeCP2 acting on ADAM10/NOTCH signaling, implicating that molecules in this pathway are important for the etiology of MDS and possibly for ASD
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