Species and cell-type properties of classically defined human and rodent neurons and glia

Xu, Xiao; Stoyanova, Elitsa I; Lemiesz, Agata E.; Xing, Jie; Mash, Deborah C.; Heintz, Nathaniel

doi:10.7554/elife.37551

Cited by 71 publications

(86 citation statements)

References 111 publications

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“…This work conducted at the tissue level is consistent with our results showing that mouse shared BCCMs with human, but the BCCMs of the human brain were human-specific, except the neuron-related module. Our results also supported a recently published work at the single-cell level by Xu et al who observed that hundreds of orthologous gene differences between human and rodent were cell type-specific 42 . Our data add to accumulating evidence that human have more cell-specific co-expression modules than mouse.…”

Section: Discussionsupporting

confidence: 92%

Evaluating brain cell marker genes based on differential gene expression and co-expression

Dai

Chen

Jiao

et al. 2019

Preprint

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12Reliable identification of brain cell types is necessary for studying brain cell 13 biology. Many brain cell marker genes have been proposed, but their reliability 14 has not been fully validated. We evaluated 540 commonly-used marker genes 15 of astrocyte, microglia, neuron, and oligodendrocyte with six transcriptome and 16 proteome datasets from purified human and mouse brain cells (n=125). By 17 setting new criteria of cell-specific fold change, we identified 22 gold standard 18 marker genes (GSM) with stable cell-specific expression. Our results call into 19 question the specificity of many proposed marker genes. We used two single-20 cell transcriptome datasets from human and mouse brains to explore the co-21 expression of marker genes (n=3337). The mouse co-expression modules were 22 perfectly preserved in human transcriptome, but the reverse was not. Also, we 23 proposed new criteria for identifying marker genes based on both differential 24 expression and co-expression data. We identified 16 novel candidate marker 25 genes (NCM) for mouse and 18 for human independently, which have the 26 potential for use in cell sorting or other tagging techniques. We validated the 27 specificity of GSM and NCM by in-silico deconvolution analysis. Our systematic 28 evaluation provides a list of credible marker genes to facilitate correct cell 29 identification, cell labeling, and cell function studies. 30 31 development of marker genes, which are sets of genes that express specifically 41 in a cell type. Thousands of genes have been proposed as marker genes 2 . One 42 well-known marker gene, RBFOX3 (gene of NeuN), is only expressed in nuclei 43 of most neuronal cell types 3 . Marker genes can be used in several applications. 44Protein products of marker genes can be used to label different cell types, which 45 may be used in fluorescence activated cell sorting (FACS). Marker genes also 46 can be used to determine cell composition in bulk tissue samples. A 47 computational method known as supervised deconvolution was developed to 48 infer cell proportions in bulk tissue samples based on the expression of marker 49 genes 4-6 . This method has been applied to studying the composition of bulk 50 brain samples 7,8 . High specificity of marker genes is critical for generating 51 reliable results in all of these applications. 52Differential gene expression (DGE) analysis of transcriptome or proteome 53 data is the most straightforward way to define the specificity of marker genes 9-54 15 . One of the drawbacks of DGE is that the outcomes is study-dependent. The 55 outcomes are affected by many factors such as species, cell or tissue source, 56 and the data generation platform. Human and mouse genomes are 80% 57 orthologous 16 , but differences in gene expression between species are often 58 greater than those between tissues within one species 17 . Within a species, cells 59 isolated from primary culture or acutely from tissue showed different gene 60 expression patterns 18 . Also, the expression estimates of the mar...

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Section: Discussionsupporting

confidence: 92%

Evaluating brain cell marker genes based on differential gene expression and co-expression

Dai

Chen

Jiao

et al. 2019

Preprint

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“…Translational profiling of hPSC-PCs and mouse PCs captured species-specific gene expression, consistent with findings of differential gene expression between human and rodent cerebellar cells (59). Two types of species-specific gene expression were observed, expression of primate-specific genes in hPSC-PCs that are non-existent in mouse, and upregulation of genes in hPSC-PCs compared to background levels of expression in mouse PCs.…”

Section: Discussionsupporting

confidence: 75%

Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics

Buchholz

Carroll

Kocabas

et al. 2020

Preprint

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Comparative transcriptomics between differentiating human pluripotent stem cells (hPSC) and developing mouse neurons offers a powerful approach to compare genetic and epigenetic pathways in human and mouse neurons. To analyze human Purkinje cell (PC) differentiation, we optimized a protocol to generate hPSC-PCs that formed synapses when cultured with mouse cerebellar glia and granule cells and fired large calcium currents, measured with the genetically encoded calcium indicator jRGECO1a. To directly compare global gene expression of hPSC-PCs with developing mouse PCs, we used translating ribosomal affinity purification (TRAP). As a first step, we used Tg(Pcp2-L10a-Egfp) TRAP mice to profile actively transcribed genes in developing postnatal mouse PCs, and used metagene projection to identify the most salient patterns of PC gene expression over time. We then created a transgenic Pcp2-L10a-Egfp

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“…To corroborate this finding, Purkinje cells will need to be isolated across a series of embryonic and postnatal time points to identify gene signatures that distinguish subtypes. Likewise, the level of expression of another transcription factor, OLIG2, in the cerebellar oligodendrocyte lineage discriminates between mature oligodendrocytes and immature oligodendrocyte progenitors [47].…”

Section: Development Of Cerebellar Neuronal Subtypesmentioning

confidence: 99%

“…In parallel with the ultrastructural differences between mouse and human germinal zones, genomic methods have been employed to compare cerebellar neurons and glia between these species [47,71]. Independent analyses using single-nucleus droplet-based sequencing (snDrop-seq) [71] or sequencing of pooled nuclei from distinct subpopulations of cells (nucRNA-seq) [47] showed variable outcomes in identifying major homologous differentiated cell types in human postmortem brain tissue. In particular, the rare Purkinje cell population could not be identified in the former study [71] but was detected using the latter approach [47].…”

Section: Divergent Rodent and Human Cerebellar Neuronal Subtype Specimentioning

confidence: 99%

Deconstructing cerebellar development cell by cell

et al. 2020

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The cerebellum is a pivotal centre for the integration and processing of motor and sensory information. Its extended development into the postnatal period makes this structure vulnerable to a variety of pathologies, including neoplasia. These properties have prompted intensive investigations that reveal not only developmental mechanisms in common with other regions of the neuraxis but also unique strategies to generate neuronal diversity. How the phenotypically distinct cell types of the cerebellum emerge rests on understanding how gene expression differences arise in a spatially and temporally coordinated manner from initially homogeneous cell populations. Increasingly sophisticated fate mapping approaches, culminating in genetic-induced fate mapping, have furthered the understanding of lineage relationships between early-versus later-born cells. Tracing the developmental histories of cells in this way coupled with analysis of gene expression patterns has provided insight into the developmental genetic programmes that instruct cellular heterogeneity. A limitation to date has been the bulk analysis of cells, which blurs lineage relationships and obscures gene expression differences between cells that underpin the cellular taxonomy of the cerebellum. This review emphasises recent discoveries, focusing mainly on single-cell sequencing in mouse and parallel human studies that elucidate neural progenitor developmental trajectories with unprecedented resolution. Complementary functional studies of neural repair after cerebellar injury are challenging assumptions about the stability of postnatal cellular identities. The result is a wealth of new information about the developmental mechanisms that generate cerebellar neural diversity, with implications for human evolution.

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Species and cell-type properties of classically defined human and rodent neurons and glia

Cited by 71 publications

References 111 publications

Evaluating brain cell marker genes based on differential gene expression and co-expression

Evaluating brain cell marker genes based on differential gene expression and co-expression

Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics

Deconstructing cerebellar development cell by cell

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