Comprehensive transcriptome analysis of neocortical layers in humans, chimpanzees and macaques

He, Zhisong; Han, Dingding; Efimova, Olga; Guijarro, Patricia; Yu, Qianhui; Oleksiak, Anna; Jiang, Sufei; Anokhin, Konstantin V.; Velichkovsky, Boris M.; Grünewald, Stefan; Khaitovich, Philipp

doi:10.1038/nn.4548

Cited by 121 publications

(137 citation statements)

References 46 publications

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“…These data are so far consistent with oligodendrocytes being the large majority of all non-neuronal cells across brain structures and species, including cortical gray matter [81,87], but possibly also constituting a variable percentage of the non-neuronal cell population. The somewhat variable densities of astrocytes across species are also compatible with the earlier finding that human astrocytes appear larger than mouse astrocytes [86].…”

Section: Relative Frequencies Of Glial Cell Subtypessupporting

confidence: 74%

You Do Not Mess with the Glia

Herculano‐Houzel

Santos

2018

Neuroglia

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Vertebrate neurons are enormously variable in morphology and distribution. While different glial cell types do exist, they are much less diverse than neurons. Over the last decade, we have conducted quantitative studies of the absolute numbers, densities, and proportions at which non-neuronal cells occur in relation to neurons. These studies have advanced the notion that glial cells are much more constrained than neurons in how much they can vary in both development and evolution. Recent evidence from studies on gene expression profiles that characterize glial cells-in the context of progressive epigenetic changes in chromatin during morphogenesis-supports the notion of constrained variation of glial cells in development and evolution, and points to the possibility that this constraint is related to the late differentiation of the various glial cell types. Whether restricted variation is a biological given (a simple consequence of late glial cell differentiation) or a physiological constraint (because, well, you do not mess with the glia without consequences that compromise brain function to the point of rendering those changes unviable), we predict that the restricted variation in size and distribution of glial cells has important consequences for neural tissue function that is aligned with their many fundamental roles being uncovered.

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Section: Relative Frequencies Of Glial Cell Subtypessupporting

confidence: 74%

You Do Not Mess with the Glia

Herculano‐Houzel

Santos

2018

Neuroglia

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“…The analysis of the relative expression of FEZF2 across cortical sections confirmed its enrichment in layer 5. AKAP9, ASH1L and SCN2A were relatively more expressed in deeper sections of layer 5 but, contrary to FEZF2, none of them can be considered as significant layer specific markers in humans (51). KAT2B and DIP2A…”

Section: Spatiotemporal Co-expression Of Mutated High-risk Genes Inmentioning

confidence: 90%

“…RPKM from the 17 cortical sections were obtained from He et al 2017 (51). To represent relative expression across sections for each gene, we scaled RPKM values to be between 0 and 1 by subtracting the minimum and dividing by the maximum minus the minimum.…”

Section: Cortical Layer Expressionmentioning

confidence: 99%

“…Family 21 whose autistic child displayed the transmitted mutation in the KTNAL2 gene. †de NOVO SNV, § transmitted SNV, * CNV We used data from He et al 2017, to create a layer expression profile for FEZF2 and nine other ASD associated genes. The expression of FEZF2 appears restricted to layer 5.…”

Section: Figure 6 Multiple Damaging Mutations In the High-risk Genesmentioning

confidence: 99%

“…We used data from the adult human brain (He et al 2017) to obtain profiles for FEZF2 and ten other ASD associated genes.…”

Section: Supplementary Figure 6 Multiple Sequence Alignment Of Znf55mentioning

confidence: 99%

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Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Bensaid

Loe-Mie

Lepagnol-Bestel

et al. 2019

Preprint

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words)Autism Spectrum Disorders (ASDs) are a heterogeneous collection of neurodevelopmental disorders with a strong genetic basis. Recent studies identified that a single hit of either a de novo or transmitted gene-disrupting, or likely gene-disrupting, mutation in a subset of 65 strongly associated genes can be sufficient to generate an ASD phenotype. We took advantage of consanguineous families with an ASD proband to evaluate this model. By a genome-wide homozygosity mapping of ten families with eleven children displaying ASD, we identified a linkage region of 133 kb in five families at the 3p14.2 locus that includes FEZF2 with a LOD score of 5.8 suggesting a founder effect. Sequencing FEZF2 revealed a common deletion of four codons. However, the damaging FEZF2 mutation did not appear to be sufficient to induce the disease as non-affected parents also carry the mutation and, similarly, Fezf2 knockout mouse embryos electroporated with the mutant human FEZF2 construct did not display any obvious defects in the corticospinal tract, a pathway whose development depends on FEZF2. We extended the genetic analysis of these five FEZF2-linked families versus five FEZF2 non-linked families by studying de novo and transmitted copy number variation (CNV) and performing Whole Exome Sequencing (WES). We identified damaging mutations in the subset of 65 genes strongly associated with ASD whose co-expression analysis suggests an impact on the prefrontal cortex during the mid-fetal periods. From these results, we propose that both FEZF2 deletion and multiple hits in the repertoire of these 65 genes are necessary to generate an ASD phenotype. Significance Statement (120 words)The human neocortex is a highly organized laminar structure with neuron positioning and identity of deep-layer cortical neurons that depend on key transcription factors, such as FEZF2, SATB2, TSHZ3 and TBR1. These genes have a specific spatio-temporal pattern of expression in human midfetal deep cortical projection neurons and display mutations in patients with Autism Spectrum Disorder (ASD). Here, we identified a linkage region involving FEZF2 gene in five consanguineous families with an ASD proband. For these FEZF2-allele linked probands, we identified a four-codon deletion in FEZF2 and damaging mutations in other high-risk ASD genes, that exhibit regional and cell type-specific convergence in neocortical deep-layer excitatory neurons, suggesting a multi-hit genomic architecture of ASD in these consanguineous families.

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Mechanisms of radial glia progenitor cell lineage progression

2017

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The mammalian cerebral cortex is responsible for higher cognitive functions such as perception, consciousness, and acquiring and processing information. The neocortex is organized into six distinct laminae, each composed of a rich diversity of cell types which assemble into highly complex cortical circuits. Radial glia progenitors (RGPs) are responsible for producing all neocortical neurons and certain glia lineages. Here, we discuss recent discoveries emerging from clonal lineage analysis at the single RGP cell level that provide us with an inaugural quantitative framework of RGP lineage progression. We further discuss the importance of the relative contribution of intrinsic gene functions and non‐cell‐autonomous or community effects in regulating RGP proliferation behavior and lineage progression.

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Comprehensive transcriptome analysis of neocortical layers in humans, chimpanzees and macaques

Cited by 121 publications

References 46 publications

You Do Not Mess with the Glia

You Do Not Mess with the Glia

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Mechanisms of radial glia progenitor cell lineage progression

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