MECP2 mutations rewire human ESC fate and bias cortical lineage commitment

Area of Science:

• Developmental biology
• Neuroscience
• Genetics

Background:

• Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the MECP2 gene.
• The earliest molecular events driving Rett syndrome pathogenesis remain poorly understood.

Purpose of the Study:

• To investigate the earliest molecular and developmental alterations in human cells with MECP2 mutations.
• To identify potential therapeutic targets for Rett syndrome.

Main Methods:

• Utilized isogenic human embryonic stem cell (hESC) models with three patient-derived MECP2 mutations.
• Tracked transcriptomic changes from pluripotency through neuroectoderm and neural stem/progenitor cell stages.
• Employed single-cell/bulk profiling, single-nucleus RNA-seq in cerebral organoids.

Main Results:

• Identified a shared secondary transcriptional program in MECP2-mutant cells enriched for synaptic and extracellular matrix genes.
• Observed a partial naïve-like drift in MECP2-mutant hESCs, indicated by ZFP42/REX1 upregulation.
• Found aberrant EMX1 expression trajectory (early repression followed by overshoot) across multiple Rett models.
• Discovered allele-specific but convergent disturbances in cortical lineage allocation in organoids.

Conclusions:

• MECP2 mutations initiate a continuous developmental trajectory with distinct molecular changes.
• Naïve-like cellular state and mis-timed EMX1 expression are early, tractable entry points for understanding Rett syndrome.
• These findings provide a foundation for developing targeted interventions for Rett syndrome.