Human cortical mosaicoids reveal impact on spatial organization and progressive loss of cross-genotype functional coupling in MECP2 mosaicism

MECP2 mosaic cortical mosaicoids show mutation-specific spatial segregation and a progressive loss of cross-genotype functional coupling, with wild-type neuron pairs exhibiting stronger activity coupling than mutant pairs.

• Why it matters: MECP2 mosaicism contributes to variable Rett syndrome phenotypes, yet its effects on human cortical organization and circuit assembly are not well defined.
• What they did: The study built MosaicoidX by co-seeding FACS-sorted isogenic wild-type and MECP2-mutant hiPS cells to generate genotype-resolved cortical mosaicoids, then used two-photon imaging, computational modeling, and single-cell RNA-seq with ligand-receptor analysis.
• The result: MECP2[V247X] mosaicoids showed stronger skewing of radial and angular segregation than MECP2[R306C], and genotype-resolved calcium imaging found asymmetric activity-coupled interactions, while transcriptomics implicated altered GABAergic and neurexin-neuroligin synaptic signaling.

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