Deciphering the functional specialization of whole-brain spatiomolecular gradients in the adult brain
Open accessPublished version of a preprint
Abstract
Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, whether similar gradients are maintained in the adult brain remains unknown. Here, we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral, and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately reconstructs the position of brain tissue samples, ii) delineates known functional territories, and iii) can model the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical axes differentiating the primary sensory cortex from the association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two nonhuman primate datasets and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well-known transcription factors (e.g., PAX6 and SIX3 ), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.
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Cites
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- Authors
- Vogel, J. W., Alexander-Bloch, A. F., Wagstyl, K., Bertolero, M. A., Markello, R. D., Pines, A., Sydnor, V. J., Diaz-Papkovich, A., Hansen, J. Y., Evans, A. C., Bernhardt, B., Misic, B., Satterthwaite, T. D., & Seidlitz, J.
- Affiliations
- Lund University (SE)
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104
- Wellcome Centre for Human Neuroimaging (GB)
- University of Pennsylvania (US)
- Montreal Neurological Institute and Hospital (CA)
- McGill Genome Centre (CA)
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Vogel, Jacob W.
- Satterthwaite, Theodore D.
- Seidlitz, Jakob
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2024-06-11
- Volume
- 121
- Issue
- 25
- Pages
- e2219137121-e2219137121
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC11194492
- OpenAlex
- W4399529545
- Cited by
- 34
- References
- 12
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 3 · 2023: 5 · 2022: 1
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Mental Health (T32MH019112)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- adult human brain, dorsal-ventral axis, transcription factors, Pax6, Six3, functional brain regions, local field potentials, non-human primate brain
- MeSH terms
- PAX6 Transcription Factor, Adult, Animals, Brain, Female, Humans, Male, Nerve Tissue Proteins, Transcription Factors, Gene Expression Regulation, Developmental, Body Patterning
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