Genes Expressed in Specific Areas of the Human Fetal Cerebral Cortex Display Distinct Patterns of Evolution
Open accessAbstract
The developmental mechanisms through which the cerebral cortex increased in size and complexity during primate evolution are essentially unknown. To uncover genetic networks active in the developing cerebral cortex, we combined three-dimensional reconstruction of human fetal brains at midgestation and whole genome expression profiling. This novel approach enabled transcriptional characterization of neurons from accurately defined cortical regions containing presumptive Broca and Wernicke language areas, as well as surrounding associative areas. We identified hundreds of genes displaying differential expression between the two regions, but no significant difference in gene expression between left and right hemispheres. Validation by qRTPCR and in situ hybridization confirmed the robustness of our approach and revealed novel patterns of area- and layer-specific expression throughout the developing cortex. Genes differentially expressed between cortical areas were significantly associated with fast-evolving non-coding sequences harboring human-specific substitutions that could lead to divergence in their repertoires of transcription factor binding sites. Strikingly, while some of these sequences were accelerated in the human lineage only, many others were accelerated in chimpanzee and/or mouse lineages, indicating that genes important for cortical development may be particularly prone to changes in transcriptional regulation across mammals. Genes differentially expressed between cortical regions were also enriched for transcriptional targets of FoxP2, a key gene for the acquisition of language abilities in humans. Our findings point to a subset of genes with a unique combination of cortical areal expression and evolutionary patterns, suggesting that they play important roles in the transcriptional network underlying human-specific neural traits.
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Profiling of mid-gestational human brain identified many genes differentially expressed between major regions, including genes associated with human-accelerated conserved noncoding sequences.
“Profiling of mid-gestational human brain3,5 identified many genes differentially expressed between major regions, including genes associated with human-accelerated conserved noncoding sequences (haCNSs)15.”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [5]
CNSs are typically located by genes important for developmental regulation, and many show significant enhancer activity in brain.
“CNSs are typically located by genes important for developmental regulation, and many show significant enhancer activity in brain5.”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [5]
Genes near haCNSs are particularly likely to show differential expression between regions of developing human neocortex, suggesting transcriptional regulation by haCNSs may be important in human-specific neurodevelopment.
“Genes near CNSs with significantly accelerated rates of substitution in the human lineage (haCNSs)15 are particularly likely to show differential expression between regions of developing human neocortex3,5, suggesting transcriptional regulation by haCNSs may be important in human-specific neurodevelopment.”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [5]
Prior studies have examined only a restricted subset of prenatal human brain regions and cortical layers.
“Several recent studies have assayed a limited set of brain structures1,3–5 and layers2 from prenatal human brain.”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [5]
Regional/areal transcriptional profiles were largely bilaterally symmetrical across the two hemispheres at population-level during fetal, early postnatal development and adulthood.
“Interestingly, these regional/areal transcriptional profiles were largely bilaterally symmetrical across the two hemispheres at the population-level during fetal, early postnatal development and in adulthood (Johnson et al., 2009; Kang et al., 2011; Lambert et al., 2011; Miller et al., 2014; Pletikos et al., 2014).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Lambert et al., 2011
Recent transcriptome studies have identified substantial regional/areal differences in the developing human neocortex.
“Recent transcriptome studies have identified substantial regional/areal differences in the developing human neocortex (Johnson et al., 2009; Kang et al., 2011; Lambert et al., 2011; Miller et al., 2014; Pletikos et al., 2014).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Lambert et al., 2011
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Novel Tools, Classic Techniques: Evolutionary Studies Using Primate Pluripotent Stem Cells
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- Authors
- Lambert, N., Lambot, M.-A., Bilheu, A., Albert, V., Englert, Y., Libert, F., Noel, J.-C., Sotiriou, C., Holloway, A. K., Pollard, K. S., Detours, V., & Vanderhaeghen, P.
- Affiliations
- Université Libre de Bruxelles (BE)
- Gladstone Institutes (US)
- Corresponding author
- Vanderhaeghen, Pierre
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-03-18
- Volume
- 6
- Issue
- 3
- Pages
- e17753
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3060818
- OpenAlex
- W1978937475
- Cited by
- 73
- References
- 64
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 8 · 2020: 1 · 2019: 7 · 2018: 1 · 2017: 8 · 2016: 3 · 2015: 5 · 2014: 7 · 2013: 12 · 2012: 9
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Lirias (KU Leuven) (submittedVersion, cc-by)
- Funders
- Fonds Erasme
- Waalse Gewest
- Fonds De La Recherche Scientifique - FNRS
- Services Fédéraux des Affaires Scientifiques, Techniques et Culturelles
- National Institute of General Medical Sciences (R01GM082901, #GM82901)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- cortical development, primate brain evolution, Broca's area, Wernicke's area, language evolution, FOXP2, transcriptional regulation, transcription factor binding sites, cortical layers, human-specific genes, chimpanzees, mice
- MeSH terms
- Cerebral Cortex, Biological Evolution, Humans, Regulatory Sequences, Nucleic Acid, In Situ Hybridization, Gene Expression Regulation, Developmental, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling
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