Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from...

Area of Science:

• Neuroscience
• Developmental Biology
• Stem Cell Research

Background:

• The human telencephalon's complex development and associated disorders are poorly understood.
• Identifying cellular and molecular mechanisms is crucial for understanding human-specific traits and diseases.

Purpose of the Study:

• To develop and validate human telencephalic organoids from single neural rosettes for studying development.
• To investigate transcriptional programs governing neural lineage specification.
• To model and analyze deficits in SHANK3-associated neurodevelopmental disorders.

Main Methods:

• Generation of human telencephalic organoids from stem cell-derived single neural rosettes.
• Comprehensive characterization of cell types, organization, and cytoarchitecture.
• Transcriptomic analysis to identify lineage specification programs.
• Modeling of SHANK3 hemizygosity to assess neuronal deficits.

Main Results:

• Single neural rosette-derived organoids recapitulate key features of human telencephalic development, including progenitor cells, diverse neuron types, and glial cells.
• Identified transcriptional programs underlying excitatory and inhibitory neural lineage specification from neural progenitors.
• Organoids with SHANK3 deletion showed intrinsic neuronal deficits, impaired excitatory synapses, and reduced clustered protocadherin expression.

Conclusions:

• Single neural rosette-derived organoids are a robust model for human telencephalic cortico-striatal development.
• SHANK3 hemizygosity leads to specific intrinsic, synaptic, and clustered protocadherin deficits in developing human telencephalon.
• This model provides a platform for studying neurodevelopmental disorders and potential therapeutic targets.