Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution

Area of Science:

• Neuroscience
• Developmental Biology
• Genomics

Background:

• Human brain development extends into the third decade of life, involving complex cellular and molecular changes.
• Understanding the dynamics of neural maturation is crucial for comprehending brain development and disorders.

Purpose of the Study:

• To profile gene expression and chromatin accessibility at single-cell resolution across human brain development.
• To define dynamic cellular trajectories and identify regulatory networks guiding neural maturation.
• To benchmark organoid models against human cortical development data.

Main Methods:

• Single-cell RNA sequencing and single-cell ATAC sequencing of human prefrontal cortex from gestation to adulthood.
• Integrative computational analyses to map cell type trajectories and regulatory networks.
• Benchmarking of organoid models using the generated human developmental reference data.

Main Results:

• Detailed dynamic trajectories for each cell type in the human prefrontal cortex were defined.
• Major gene expression reconfigurations occur at the prenatal-to-postnatal transition and continue into adulthood.
• Links between cellular dynamics, developmental milestones, and neurological disorder-implicated regulators were uncovered.
• Diverse timing of cell maturation and molecular convergence from different origins were characterized.

Conclusions:

• This study provides a comprehensive dynamic regulatory landscape of human cortical development.
• The findings offer insights into the timing of cell maturation and molecular convergence.
• The reference data can inform studies of neurological disorders and improve brain organoid models.