miR126-mediated alteration of vascular integrity in Rett syndrome

Area of Science:

• Neuroscience
• Vascular Biology
• Genetics

Background:

• Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in methyl-CpG binding protein 2 (MeCP2).
• MeCP2 mutations affect not only neural cells but also non-neural cells, including brain vasculature-associated endothelial cells.
• Vascular integrity is critical for brain homeostasis, and its alteration may link to neurodegenerative diseases, but its role in RTT pathogenesis is unclear.

Purpose of the Study:

• To investigate the early developmental vascular impact of MeCP2 mutations in RTT using patient-derived induced pluripotent stem (iPS) cells.
• To establish a microvascular network model to study RTT pathogenesis.
• To identify molecular mechanisms underlying vascular alterations in RTT.

Main Methods:

• Developed a microvascular network model using RTT patient-derived iPS cells with specific MeCP2 mutations (R306C, R168X) and isogenic controls.
• Utilized CRISPR/Cas9 and doxycycline-inducible ETV2 expression for expedited endothelial cell differentiation.
• Performed microRNA profiling and RNA sequencing (RNAseq) on RTT-derived endothelial cells.

Main Results:

• RTT microvascular networks exhibited significantly higher permeability compared to isogenic controls, indicating altered barrier function due to MeCP2 mutation.
• Hyperpermeability in RTT endothelial cells was associated with the upregulation of miR126-3p.
• Restoring miR126-3p levels successfully rescued the hyperpermeability phenotype.

Conclusions:

• MeCP2 mutations in RTT lead to vascular impairment mediated by miR126-3p.
• This study highlights a non-neurogenic effect of MeCP2 mutations on brain vasculature.
• Findings suggest miR126-3p as a potential therapeutic target for RTT.