Single-cell analysis of prenatal and postnatal human cortical development

Author:

Velmeshev Dmitry123ORCID,Perez Yonatan12ORCID,Yan Zihan3,Valencia Jonathan E.4ORCID,Castaneda-Castellanos David R.5,Wang Li12ORCID,Schirmer Lucas678ORCID,Mayer Simone129ORCID,Wick Brittney10,Wang Shaohui12,Nowakowski Tomasz Jan11ORCID,Paredes Mercedes2ORCID,Huang Eric J.112ORCID,Kriegstein Arnold R.12ORCID

Affiliation:

1. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.

2. Department of Neurology, University of California, San Francisco, CA 94143, USA.

3. Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA.

4. Curio Bioscience, Palo Alto, CA 94303, USA.

5. Vizgen Inc., Cambridge, MA 02138, USA.

6. Division of Neuroimmunology, Department of Neurology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.

7. Mannheim Center for Translational Neuroscience and Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.

8. Interdisciplinary Center for Neurosciences, Heidelberg University, 68167 Heidelberg, Germany.

9. Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.

10. UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA 95060, USA.

11. Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.

12. Department of Pathology, University of California, San Francisco, CA 94115, USA.

Abstract

We analyzed >700,000 single-nucleus RNA sequencing profiles from 106 donors during prenatal and postnatal developmental stages and identified lineage-specific programs that underlie the development of specific subtypes of excitatory cortical neurons, interneurons, glial cell types, and brain vasculature. By leveraging single-nucleus chromatin accessibility data, we delineated enhancer gene regulatory networks and transcription factors that control commitment of specific cortical lineages. By intersecting our results with genetic risk factors for human brain diseases, we identified the cortical cell types and lineages most vulnerable to genetic insults of different brain disorders, especially autism. We find that lineage-specific gene expression programs up-regulated in female cells are especially enriched for the genetic risk factors of autism. Our study captures the molecular progression of cortical lineages across human development.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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