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Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders
Published on: April 14, 2017
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MeCP2 regulates telencephalic development in human cerebral organoids
Miguel F Tenreiro1, Ronaldo Mohana-Borges2, Sandra M Sánchez-Sánchez1
1Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Cell Reports
|December 14, 2025
Summary
Loss of MeCP2 function causes Rett syndrome (RTT). This study shows MeCP2 is vital for prenatal brain development, impacting neuron maturation and network activity, suggesting RTT originates before birth.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Loss-of-function variants in the X-linked gene MeCP2 cause Rett syndrome (RTT), a severe syndromic autism spectrum disorder.
- While traditionally viewed as postnatal, MeCP2 is increasingly recognized for its critical prenatal role in brain development.
Purpose of the Study:
- To model early cortical development in human cerebral organoids and telencephalic assembloids lacking MeCP2.
- To investigate the prenatal impact of MeCP2 deficiency on neurodevelopment and network function.
Main Methods:
- Utilized human pluripotent stem cell-derived cerebral organoids and telencephalic assembloids.
- Analyzed transcriptional programs, morphological and functional maturation, and neuronal migration in MeCP2-deficient models.
Main Results:
- MeCP2 loss dysregulated excitatory neuron development and delayed maturation, despite intact basic cortical architecture.
- MeCP2 deficiency resulted in overproduction of cortical interneurons (cINs) with aberrant migration.
- MeCP2-deficient assembloids exhibited persistent hypersynchronous network activity.
Conclusions:
- MeCP2 is critical for early telencephalic neurodevelopment.
- These findings highlight the prenatal origins of Rett syndrome-related dysfunction.
