Abstract
Engineering brain organoids from human induced pluripotent stem cells (hiPSCs) is a powerful tool for modeling brain development and neurological disorders. Rett syndrome (RTT), a rare neurodevelopmental disorder, can greatly benefit from this technology, since it affects multiple neuronal subtypes in forebrain sub-regions. We have established dorsal and ventral forebrain organoids from control and RTT patient-specific hiPSCs recapitulating 3D organization and functional network complexity. Our data revealed a premature development of the deep-cortical layer, associated to the formation of TBR1 and CTIP2 neurons, and a lower expression of neural progenitor/proliferative cells in female RTT dorsal organoids. Moreover, calcium imaging and electrophysiology analysis demonstrated functional defects of RTT neurons. Additionally, assembly of RTT dorsal and ventral organoids revealed impairments of interneuron’s migration. Overall, our models provide a better understanding of RTT during early stages of neural development, demonstrating a great potential for personalized diagnosis and drug screening.
Highlights
Rett syndrome (RTT) is a severe neurological disorder that affects brain development and function in approximately 1 in 10.000 live births, and it is caused by mutations in the gene encoding for methyl-CpG-binding protein 2 (MeCP2)
As MeCP2 gene is located in the long arm of the X chromosome, RTT female patients are characterized by the presence of somatic mosaicism
Since female human induced pluripotent stem cells (hiPSCs) retain an inactive X-chromosome in a nonrandom pattern (Tchieu et al, 2010), it was possible to obtain an isogenic control (IC-MeCP2:R255X) from a distinct clone isolated upon reprogramming of the mosaic female cell line (Supplementary Figure 1.1A)
Summary
Rett syndrome (RTT) is a severe neurological disorder that affects brain development and function in approximately 1 in 10.000 live births, and it is caused by mutations in the gene encoding for methyl-CpG-binding protein 2 (MeCP2). MeCP2 mutations in females lead to developmental regression after 6–18 months after birth, with a range of neurodevelopmental defects, including loss of speech, acquired movement skills and severe cognitive impairment after an apparently normal hiPSCs Rett Syndrome Organoids Modeling development. RTT was modeled using neural cells differentiated from patient-specific hiPSCs with MeCP2-mutant neurons exhibiting impaired maturation, including the presence of fewer synapses, smaller soma size, altered calcium signaling, functional defects in firing activity and excitatory/inhibitory (E/I) imbalance (Marchetto et al, 2010; Ananiev et al, 2011; Fernandes et al, 2015; Tang et al, 2016). Forebrain multilineage assembloids can be patterned to contain a dorsal–ventral axis and used to recapitulate human interneuron migration (Bagley et al, 2017; Xiang et al, 2017; Sloan et al, 2018)
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