Single-Nuclei Sequencing of Late Stages of Human Brain Development and Early Postnatal Life

Project at a glance

Program

biccn

Submission status

['cell nucleus']

Funding support

Not listed

Consortium RRID

Not listed

Organizations

University of California, San Francisco

Scope

Taxa

No taxa listed

Modalities

transcriptome

Techniques

10x chromium 3' v2 sequencing

Assays

No assays listed

License

Public data available under CC BY 4.0; controlled access data subject to data use certification, None

Description

"Human cortical development spans years of prenatal and postnatal development. This incredibly complex process involves multiple interacting cell lineages and dynamic processes, such as neurogenesis and gliogenesis, neuronal migration, cell differentiation, areal specification, axon outgrowth and synapse formation and maturation. Human cortical development proceeds through a number of critical stages that are believed to be affected in neurodevelopmental and psychiatric diseases, such as autism spectrum disorder and schizophrenia. In order to investigate the dynamic landscape of human cortical development at the single-cell resolution, we utilized single-nucleus RNA sequencing (snRNA-seq) to profile more than 100 post-mortem human cortical tissue samples from over 50 individuals and three cortical areas. We included samples ranging from second and third trimesters of prenatal development though neonatal and early postnatal stages to teenage and early adult years. By using unbiased nuclei isolation coupled with droplet-based single-cell profiling (10x Genomics), we generated over 300,000 single-nucleus transcriptomics profiles. We performed unbiased clustering, marker discovery and trajectory analysis, and were able to discover gene expression programs that underlie generation of subtypes of cortical projection neurons, interneurons and glial cell types, as well as critical process of development, such as generation of astrocytes, axon outgrowth, synapse formation and formation of mature cortical neuronal circuits. By intersecting cell type-specific developmental gene expression profiles with known genetic risk factors of neurodevelopmental disorders, we were able to identify cell types and developmental stages that can be especially affected in autism spectrum disorder and schizophrenia, leading to improper formation and function of specific cortical circuits. Our study sheds light on cell type-specific mechanisms of normal cortical development and cell types and processes affected in common neurodevelopmental disease. In addition, our rich single-nucleus transcriptomic atlas will be of great value to a wide range of neuroscientists."

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