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Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders
Published on: April 14, 2017
Cerebral organoid and mouse models reveal a RAB39b-PI3K-mTOR pathway-dependent dysregulation of cortical development
1Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California 90033, USA.
Abstract:
Dysregulation of early neurodevelopment is implicated in macrocephaly/autism disorders. However, the mechanism underlying this dysregulation, particularly in human cells, remains poorly understood. Mutations in the small GTPase gene RAB39b are associated with X-linked macrocephaly, autism spectrum disorder (ASD), and intellectual disability. The in vivo roles of RAB39b in the brain remain unknown. We generated Rab39b knockout (KO) mice and found that they exhibited cortical neurogenesis impairment, macrocephaly, and hallmark ASD behaviors, which resembled patient phenotypes. We also produced mutant human cerebral organoids that were substantially enlarged due to the overproliferation and impaired differentiation of neural progenitor cells (NPCs), which resemble neurodevelopmental deficits in KO mice. Mechanistic studies reveal that RAB39b interacts with PI3K components and its deletion promotes PI3K-AKT-mTOR signaling in NPCs of mouse cortex and cerebral organoids. The mTOR activity is robustly enhanced in mutant outer radial glia cells (oRGs), a subtype of NPCs barely detectable in rodents but abundant in human brains. Inhibition of AKT signaling rescued enlarged organoid sizes and NPC overproliferation caused by RAB39b mutations. Therefore, RAB39b mutation promotes PI3K-AKT-mTOR activity and alters cortical neurogenesis, leading to macrocephaly and autistic-like behaviors. Our studies provide new insights into neurodevelopmental dysregulation and common pathways associated with ASD across species.
Insights
Mutations in RAB39b cause macrocephaly and autism spectrum disorder (ASD) by disrupting brain development. Inhibiting AKT signaling in human organoids reversed these effects, revealing a key mechanism.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Early neurodevelopmental dysregulation is linked to macrocephaly and autism spectrum disorder (ASD).
- The precise mechanisms, especially in human cells, are not fully understood.
- Mutations in the small GTPase gene RAB39b are associated with X-linked macrocephaly, ASD, and intellectual disability.
Purpose of the Study:
- To investigate the in vivo roles of RAB39b in brain development.
- To elucidate the molecular mechanisms underlying RAB39b-associated neurodevelopmental disorders.
- To explore potential therapeutic targets for RAB39b-related conditions.
Main Methods:
- Generation of Rab39b knockout (KO) mice to study in vivo brain development.
- Creation of mutant human cerebral organoids to model neurodevelopmental deficits.
- Analysis of PI3K-AKT-mTOR signaling pathways in neural progenitor cells (NPCs) and outer radial glia (oRGs).
- Pharmacological inhibition of AKT signaling to assess rescue effects.
Main Results:
- Rab39b KO mice displayed cortical neurogenesis impairment, macrocephaly, and ASD-like behaviors.
- Mutant human cerebral organoids showed overproliferation and impaired differentiation of NPCs, leading to enlargement.
- RAB39b deletion was found to promote PI3K-AKT-mTOR signaling in NPCs and oRGs.
- Enhanced mTOR activity was observed in mutant oRGs, a key cell type in human brain development.
- Inhibition of AKT signaling successfully rescued the enlarged organoid size and NPC overproliferation.
Conclusions:
- RAB39b mutation disrupts cortical neurogenesis by promoting PI3K-AKT-mTOR signaling, leading to macrocephaly and autistic-like behaviors.
- These findings provide insights into the neurodevelopmental mechanisms underlying ASD and related disorders.
- The study highlights conserved pathways affected by RAB39b mutations across species and suggests AKT signaling as a potential therapeutic target.
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