Single-cell analysis of prenatal and postnatal human cortical development

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Human brain development involves complex cellular differentiation and lineage specification.
• Understanding these processes is crucial for identifying disease vulnerabilities.

Purpose of the Study:

• To map lineage-specific gene expression programs during human prenatal and postnatal brain development.
• To identify regulatory networks controlling cortical cell fate.
• To determine cell types most vulnerable to genetic risk factors for brain disorders, especially autism.

Main Methods:

• Analysis of over 700,000 single-nucleus RNA sequencing profiles from 106 donors.
• Leveraging single-nucleus chromatin accessibility data to delineate gene regulatory networks.
• Intersecting developmental data with genetic risk factors for human brain diseases.

Main Results:

• Identification of lineage-specific programs for excitatory neurons, interneurons, glial cells, and vasculature.
• Delineation of enhancer-gene regulatory networks and transcription factors governing cortical lineage commitment.
• Identification of specific cortical cell types and lineages most susceptible to genetic insults, with a focus on autism spectrum disorder.
• Discovery that autism genetic risk factors are enriched in lineage-specific programs upregulated in female cells.

Conclusions:

• This study provides a comprehensive molecular atlas of human cortical lineage progression during development.
• It highlights specific cell types and developmental stages vulnerable to neurodevelopmental disorders.
• Findings offer insights into the cellular basis of autism, particularly sex-specific genetic influences.