A cross-species proteomic map reveals neoteny of human synapse development
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Abstract
The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood 1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.
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In human, macaque, and mouse cerebral cortex, SRGAP2(A) and SYNGAP1 synaptic abundance show inverted trajectories across developmental stages.
“Analysis of a recently published dataset50 of postsynaptic protein abundance across developmental stages in human, macaque, and mouse cerebral cortex, which revealed the same inverted trajectories of SRGAP2(A) and SYNGAP1 synaptic abundance in all species (Figure S10G).”
From Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition (2024) · cites this paper as [50]
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Self-citation
- Authors
- Wang, L., Pang, K., Zhou, L., Cebrián-Silla, A., González-Granero, S., Wang, S., Bi, Q., White, M. L., Ho, B., Li, J., Li, T., Perez, Y., Huang, E. J., Winkler, E. A., Paredes, M. F., Kovner, R., Sestan, N., Pollen, A. A., Liu, P., Li, J., Piao, X., García-Verdugo, J. M., Alvarez-Buylla, A., Liu, Z., & Kriegstein, A. R.
- Affiliations
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- Universitat de València (ES)
- Yale University (US)
- University of Massachusetts Lowell (US)
- Corresponding author
- Wang, Li
- Kriegstein, Arnold R.
- ORCID
- Venue
- Nature
- Published
- 2023-09-13
- Volume
- 622
- Issue
- 7981
- Pages
- 112-119
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10576238
- OpenAlex
- W4386697742
- Cited by
- 82
- References
- 112
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 24 · 2023: 8
- FWCI
- 9.94
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion, cc-by-nc)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (1s10rr025622-01)
- National Institute of Mental Health (U01MH124619, K99MH131832)
- National Human Genome Research Institute (R01HG010898)
- National Institute of Neurological Disorders and Stroke (R35NS097305, P01NS083513, R01NS028478)
- National Center for Research Resources (S10 RR025622)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- synaptic development, postsynaptic density, neoteny, human brain evolution, dendritic spine maturation, RhoGEF, neocortex, developmental timing, synapse maturation
- MeSH terms
- Adolescent, Animals, Child, Child, Preschool, Cognition, Gestational Age, Humans, Infant, Infant, Newborn, Macaca, Neurons, Species Specificity, Synapses, Signal Transduction, Proteomics, Dendritic Spines, Mice, Young Adult, Post-Synaptic Density, Rho Guanine Nucleotide Exchange Factors
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