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Patterns of gene expression and evolution in the human developing cerebral cortex

ABSTRACT: The cerebral cortex underwent a rapid expansion and complexification during recent primate evolution, but the underlying developmental mechanisms remain essentially unknown. In order to uncover genetic networks underlying the development of the human cerebral cortex, we profiled the transcriptome of human fetal cortical domains containing language areas of Broca and Wernicke, as well as associative areas. We thus identified hundreds of genes displaying differential expression between the two areas or between distinct temporal stages. A subset of these genes was further validated by qRTPCR and in situ hybridization, revealing novel patterns of area and layer-specific expression throughout the developing cortex at midgestation, a critical period of cortical patterning. Computational genomic analyses revealed that the proportion of genes located close to evolutionarily accelerated regions was far more abundant among the genes differentially expressed between the two cortical areas examined, but not among those differentially expressed between different stages of development. In silico screening enabled to identify accelerated regions displaying increased turnover of change in transcription factor binding sites, which were enriched among those closer to genes differentially expressed between cortical areas. Overall our work points to the identification of cortical genes that display a unique combination of patterns of evolution and expression, which may constitute an important part of the genetic framework underlying human-specific neural traits and diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE21858 | GEO | 2011/06/01

SECONDARY ACCESSION(S): PRJNA127037

REPOSITORIES: GEO

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Patterns of gene expression and evolution in the human developing cerebral cortex

Project description:The cerebral cortex underwent a rapid expansion and complexification during recent primate evolution, but the underlying developmental mechanisms remain essentially unknown. In order to uncover genetic networks underlying the development of the human cerebral cortex, we profiled the transcriptome of human fetal cortical domains containing language areas of Broca and Wernicke, as well as associative areas. We thus identified hundreds of genes displaying differential expression between the two areas or between distinct temporal stages. A subset of these genes was further validated by qRTPCR and in situ hybridization, revealing novel patterns of area and layer-specific expression throughout the developing cortex at midgestation, a critical period of cortical patterning. Computational genomic analyses revealed that the proportion of genes located close to evolutionarily accelerated regions was far more abundant among the genes differentially expressed between the two cortical areas examined, but not among those differentially expressed between different stages of development. In silico screening enabled to identify accelerated regions displaying increased turnover of change in transcription factor binding sites, which were enriched among those closer to genes differentially expressed between cortical areas. Overall our work points to the identification of cortical genes that display a unique combination of patterns of evolution and expression, which may constitute an important part of the genetic framework underlying human-specific neural traits and diseases. We determined gene expression patterns in cortical domains that contain areas thought to have undergone significant divergence during primate evolution, including language areas of Broca and Wernicke, as well as association areas of the frontal and parieto-temporal cortex in the right and left sides of human fetal brains at 17 and 19 gestional weeks.

2011-06-01 | E-GEOD-21858 | biostudies-arrayexpress

TRNP1 regulates expansion and folding of the mammalian cerebral cortex by control of radial glial fate

Project description:Evolution of the mammalian brain encompassed a remarkable increase in size of cerebral cortex, including tangential and radial expansion, but the mechanisms underlying these key parameters are still largely unknown. Here, we identified the novel DNA associated protein TRNP1 as a regulator of cerebral cortical expansion in both these dimensions. Gain and loss of function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion, while lower levels promote radial expansion resulting in a potent increase in the generation of intermediate progenitors and outer radial glial cells resulting in folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences also in the cerebral cortex of human fetuses anticipating radial or tangential expansion respectively. Thus, the dynamic regulation of TRNP1 is critical to regulate tangential and radial expansion of the cerebral cortex in mammals. We performed gene expression microarray analysis on embryonic mouse cerebral cortex derived from Trnp1 knockdown and control animals.

2013-04-26 | E-GEOD-40582 | biostudies-arrayexpress

Transcription profiling by array of rat cortex regions

Project description:The neocortex of the mammalian brain is comprised by six distinct layers with neuronal subtypes that appear indistinguishable from one cortical area to the next. Correspondingly, global gene expression seems to be almost identical across the cerebral cortex and only a few genes have so far been reported to show regional enrichment in specific cortical areas. In the present study on adult rat brain, we have corroborated the strikingly similar gene expression among cortical areas. However, differential expression analysis has allowed for the identification of 30, 24 and 11 genes enriched in frontomedial -, temporal- or occipital cortex, respectively. A large proportion of these 65 genes appear to be involved in signal transduction, including the ion channel Fxyd6, the neuropeptide Grp and the nuclear receptor Rorb. We also find that the majority of these genes display increased expression levels around birth and show distinct preferences for certain cortical layers and cell types in rodents. Since specific patterns of expression often are linked to equally specialised biological functions, we propose that these cortex sub-region enriched genes are important for proper functioning of the cortical regions in question and may represent interesting candidates for further genetic studies of neuropsychiatric phenotypes.

2010-12-31 | E-TABM-1019 | biostudies-arrayexpress

TRNP1 regulates expansion and folding of the mammalian cerebral cortex by control of radial glial fate

2013-04-26 | GSE40582 | GEO

Massively Parallel Genetic Disruption of Enhancers Active During Human Corticogenesis

Project description:Changes in gene regulation have been linked to the expansion of the human cerebral cortex and to neurodevelopmental disorders. However, the biological effects of genetic variation within developmental regulatory elements on human corticogenesis are not well understood. We used sgRNA-Cas9 genetic screens in human neural stem cells (hNSCs) to disrupt 10,674 expressed genes and 2,227 enhancers active in the developing human cortex and determine the resulting effects on cellular proliferation. Gene disruptions affecting proliferation were enriched for genes associated with risk for human neurodevelopmental phenotypes including primary microcephaly and autism spectrum disorder. Although disruptions in enhancers had overall weaker effects on proliferation than gene disruptions, we identified enhancer disruptions that severely perturbed hNSC self-renewal. Disruptions in Human Accelerated Regions and Human Gain Enhancers, regulatory elements implicated in the evolution of the human brain, also perturbed hNSC proliferation, establishing a role for these elements in human neurodevelopment. Integrating proliferation phenotypes with chromatin interaction maps revealed regulatory relationships between enhancers and target genes that contribute to neurogenesis and potentially to human cortical evolution.

2019-12-03 | GSE138823 | GEO

Hominin-specific NOTCH2 paralogs expand human cortical neurogenesis through regulation of Delta/Notch interactions.

Project description:The human cerebral cortex has undergone rapid expansion and increased complexity during recent evolution. Hominid-specific gene duplications represent a major driving force of evolution, but their impact on human brain evolution remains unclear. Using tailored RNA sequencing (RNAseq), we profiled the spatial and temporal expression of Hominid-specific duplicated (HS) genes in the human fetal cortex, leading to the identification of a repertoire of 36 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among these we focused on NOTCH2NL, previously uncharacterized HS paralogs of NOTCH2. NOTCH2NL promote the clonal expansion of human cortical progenitors by increasing self-renewal, ultimately leading to higher neuronal output. NOTCH2NL function by activating the Notch pathway, through inhibition of Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes linking genomic evolution to human brain development, and reveals how hominin-specific NOTCH paralogs may have contributed to the expansion of the human cortex. The dataset contains raw sequences (FASTQ files) from the Illumina 2x150bp paired-end RNA sequencing profiles of 11 fetal human brain samples at 7, 9, 12, 15 and 21 gestational weeks.

| EGAS00001002798 | EGA

Genetics of Human Developmental Brain Disorders

Project description:<p>Developmental brain malformations are at the core of significant neurological diseases affecting many families in the United States and around the world. It is known that epilepsy, specific learning deficits and intellectual disability, cerebral palsy, and abnormalities of brain volume can be attributed in many cases to pathological malformations of the cerebral cortex. Although these consequences, such as epilepsy and intellectual disability, might appear broadly in the population as due to complex traits, this study's focus on those associated with cortical malformations highlights individual developmental pathways likely represented by innumerable and rare Mendelian alleles. Research has thus far uncovered dozens of genes responsible for these conditions and dissected the mechanisms underlying early cortical development in animals. However, this progress represents only the dawn of understanding the complex genetic network and neuronal architecture of the uniquely human cerebral cortex.</p> <p>The overall goal of this study is to define the genetic bases of human cerebral cortical development. This is accomplished through (1) the ascertainment of families with disorders of human brain development and malformation, (2) categorizing these using medical, physical and neuroimaging data, and (3) mapping and identifying the gene causing the disorder of cortical development, which can then be investigated for its normal expression and function, and role in human disease. </p>

| phs000492 | dbGaP

RNA-seq to investigate how human-specific Notch2 paralogs expand cortical neurogenesis through regulation of Delta/Notch interactions.

Project description:The human cerebral cortex underwent rapid enlargement and complexification during recent evolution. Hominid-specific (HS) genes arising from genomic duplications may be involved, but it remains unclear how much and which HS genes contribute to human brain development. Using tailored RNAseq profiling, we identify a repertoire of >60 HS genes that display robust and dynamic expression during human fetal corticogenesis. Among these, Notch2NL genes stood out as human-specific Notch2 paralogs that promotes cortical progenitor maintenance. Clonal analyses of human cortical progenitors revealed that Notch2NL promotes their expansion by increasing self-renewal, ultimately leading to higher clonal neuronal output. Notch2NL acts by direct activation of the Notch pathway, through cell-autonomous inhibition of Delta/Notch interactions. Our data identify a large repertoire of newly evolved genes linking human brain development and evolution, and indicate how human-specific Notch paralogs may have contributed to the expansion of the human brain.

2018-04-06 | E-MTAB-6232 | biostudies-arrayexpress

Mitochondria Metabolism Sets the Species-Specific Tempo of Neuronal Development

Project description:Neuronal development in the human cerebral cortex is considerably prolonged compared to that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny.

2023-02-01 | GSE219253 | GEO

Neuroserpin Is Strongly Expressed in the Developing and Adult Mouse Neocortex but Its Absence Does Not Perturb Cortical Lamination and Synaptic Proteome

Project description:Neuroserpin is a serine protease inhibitor that regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin is strongly expressed during nervous system development as well as during adulthood, when it is predominantly found in regions eliciting synaptic plasticity. In the hippocampus, neuroserpin regulates developmental neurogenesis, synaptic maturation and in adult mice it modulates synaptic plasticity and controls cognitive and social behavior. High expression levels of neuroserpin in the cerebral cortex starting from prenatal stage and persisting during adulthood suggest an important role for the serpin in the formation of this brain region and in the maintenance of cortical functions. In order to uncover neuroserpin function in the cerebral cortex, in this work we performed a comprehensive investigation of its expression pattern during development and in the adulthood. Moreover, we assessed the role of neuroserpin in cortex formation by comparing cortical lamination and neuronal maturation between neuroserpin-deficient and control mice. Finally, we evaluated a possible regulatory role of neuroserpin at cortical synapses in neuroserpin-deficient mice. We observed that neuroserpin is expressed starting from the beginning of corticogenesis until adulthood throughout the cortex in both glutamatergic projection neurons and GABA-ergic interneurons. However, in the absence of neuroserpin we did not detect any alteration in cortical layer formation, in soma size, in dendritic length, and the ultrastructure. Furthermore no significant quantitative changes could be observed in the proteome of cortical synapses could be observed upon Neuroserpin deficiency. We conclude that, although strongly expressed in the cerebral cortex, absence of neuroserpin does not lead to developmental abnormalities, and does not perturb composition of the cortical synaptic proteome.

2021-02-23 | PXD022371 | Pride

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