The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.
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We wish to thank the Allen Institute founders, P. G. Allen and J. Allen, for their vision, encouragement and support. We express our gratitude to past and present Allen Institute staff members R. Adams, A. Alpisa, A. Boe, E. Byrnes, M. Chapin, J. Chen, C. Copeland, N. Dotson, K. Fotheringham, E. Fulfs, M. Gasparrini, T. Gilbert, Z. Haradon, N. Hejazinia, N. Ivanov, J. Kinnunen, A. Kriedberg, J. Laoenkue, S. Levine, V. Menon, E. Mott, N. Motz, J. Pendergraft, L. Potekhina, J. Redmayne-Titley, D. Rosen, C. Simpson, S. Shi, L. Velasquez, U. Wagley, N. Wong and B. Youngstrom for their technical assistance. We would also like to thank J. Augustinack, T. Benner, A. Mayaram, M. Roy, A. van der Kouwe and L. Wald from the Fischl laboratory. Also, we wish to acknowledge Covance Genomics Laboratory (Seattle, Washington) for microarray probe generation, hybridization and scanning. In addition, we express our gratitude to Advanced Bioscience Resources, for providing tissue used for expression profiling and reference atlas generation as well as to the Laboratory of Developmental Biology, University of Washington, for providing tissue used for expression profiling and reference atlas generation. The Laboratory of Developmental Biology work was supported by the National Institutes of Health (NIH) Award Number 5R24HD0008836 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. The BrainSpan project was supported by Award Number RC2MH089921 (PIs: E. Lein and M. Hawrylycz, Allen Institute for Brain Science) from the National Institute of Mental Health. The content is solely the responsibility of the respective authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health.
Extended data figures
Complete ontology for the BrainSpan project, showing the subset of structures and layers assayed in this study. Further details in the "Key" tab of the spreadsheet.
Layer of maximal expression (with statistics) for each gene in each brain (Supplementary Table 3). These data were used for Figure 2d. Enrichment analysis for laminar genes at 21pcw (Supplementary Table 4). Significantly enriched gene ontology and brain-related categories are listed. Further details in the "Key" tab of the spreadsheet.
Module assignments and module membership for each gene in the cortical network. Genes listed in Figure 3b were chosen from this table. Further details in the "Key" tab of the spreadsheet.
Enrichment analysis for genes in each cortical network module. Significantly enriched DAVID categories and relevant brain-related categories, including cell type enrichment are listed. Details are described in the worksheet labeled "Key".
Enrichment analysis for genes in each germinal network module. Significantly enriched DAVID categories and relevant brain-related categories, including cell type enrichment are listed. Details are described in the worksheet labeled "Key".
150 marker genes for human and/or mouse subplate, along with evidence for defining these genes as SP markers. Genes listed in Figure 4 were selected from this table. Further details in the "Key" tab of the spreadsheet.
All genes identified as showing frontal to temporal gradient patterning in the developing human neocortex are included. Subsets of these genes, which are associated with human accelerated conserved noncoding sequences (haCNSs) or that are consistent with mouse, are also highlighted. Further details in the "Key" tab of the spreadsheet.