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Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex

Nature Neuroscience volume 18, pages 637–646 (2015)Cite this article

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Abstract

The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans but virtually absent in rodents, called outer radial glia (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined progenitor subtype–specific sorting with transcriptome-wide RNA sequencing to identify genes enriched in human ORG, which included targets of the transcription factor neurogenin and previously uncharacterized, evolutionarily dynamic long noncoding RNAs. Activating the neurogenin pathway in ferret progenitors promoted delamination and outward migration. Finally, single-cell transcriptional profiling in human, ferret and mouse revealed more cells coexpressing proneural neurogenin targets in human than in other species, suggesting greater neuronal lineage commitment and differentiation of self-renewing progenitors. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors.

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Figure 1: Transcriptional profiling of isolated human radial glial cells distinguishes apical from non-apical subpopulations.
Figure 2: NEUROG2 regulates progenitor morphology and molecular identity in the developing cortex of the gyrencephalic ferret.
Figure 3: Single-cell gene expression of human and mouse progenitors reveals species-specific RGC subpopulations.
Figure 4: Population-level whole-transcriptome RNA-seq and single-cell expression analysis of ferret RGC.
Figure 5: Transcripts detected by RNA-seq include previously unknown lncRNAs with distinct RGC subtype expression patterns and evolutionary conservation.

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Acknowledgements

We thank J. Partlow for coordinating human tissue protocols, D. Gonzalez for animal protocol and technical experimental assistance, S. Lazo-Kallanian for single-cell FACS assistance and all members of the Walsh laboratory for comments and discussion. The Neurog2-VP16 construct was a generous gift from C. Schuurmans (University of Calgary). This work was supported by grants to C.A.W. from the US National Institutes of Neurological Disease and Stroke (R01 NS032457) and the Paul G. Allen Family Foundation. M.B.J. was supported by a fellowship from the Nancy Lurie Marks Family Foundation. P.P.W. was supported by the Stuart H.Q. & Victoria Quan Fellowship at Harvard Medical School. Single-cell expression profiling experiments were performed at the Molecular Genetics Core at Boston Children's Hospital (BCH IDDRC, P30 HD18655). Transcriptome analysis was performed using Harvard Medical School's Orchestra high-performance computing cluster, which is partially supported by US National Institutes of Health grant NCRR 1S10RR028832-01. C.A.W. is an Investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Matthew B Johnson and Peter P Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA

    Matthew B Johnson, Peter P Wang, Kutay D Atabay, Elisabeth A Murphy, Ryan N Doan & Christopher A Walsh

  2. Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA

    Matthew B Johnson, Peter P Wang, Kutay D Atabay, Elisabeth A Murphy, Ryan N Doan & Christopher A Walsh

  3. Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA

    Matthew B Johnson, Peter P Wang, Kutay D Atabay, Elisabeth A Murphy, Ryan N Doan & Christopher A Walsh

  4. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Jonathan L Hecht

  5. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Jonathan L Hecht

  6. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA

    Christopher A Walsh

  7. Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA

    Christopher A Walsh

  8. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Christopher A Walsh

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Contributions

M.B.J., P.P.W. and R.N.D. designed and conducted experiments and analyzed data. K.D.A. and E.A.M. performed experiments and analyzed data. J.L.H. procured and examined human tissue samples. M.B.J., P.P.W. and C.A.W. interpreted the data and wrote the manuscript.

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Correspondence to Christopher A Walsh.

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Integrated supplementary information

Supplementary Figure 1 Isolation of human RGC subpopulations by FACS

a, Both LG+Prhi and LG+Prlo subpopulations are enriched for known RGC-expressed genes (GFAP, VIM, GLAST, PAX6, SOX2, BLBP), and depleted for neuronal markers (DCX, TUJ1, NeuN, MEF2C). The LG+Prhi subpopulation was enriched relative to the LG+Prlo subpopulation for PROM1 transcript as well as three other transcripts encoding apical membrane domain-specific proteins (PARD3 [Par3], TJP1 [ZO-1], MPP5 [Pals]). Data represents four biological replicates (mean ± SEM) ranging from 16 WG to 23 WG. b, Primary neurospheres derived from LeX− and LeX+ cells sorted from dissociated human fetal cortex. Neurospheres were serially passaged at clonal density and immunolabeled for RGC marker SOX2.

Supplementary Figure 2 Gene set enrichment in human RGC subpopulations

Gene set enrichment analysis confirmed the RGC progenitor nature of both the LG+Prhi and LG+Prlo subpopulations, with enrichment of important progenitor signaling pathways (e.g. Wnt/Bmp/Tgf) and gene ontology terms (cell cycle control, neural development) in both subpopulations relative to LG−Pr− neurons and other cell types.

Supplementary Figure 3 Selected LG+Prlo-enriched candidate non-apical RGC genes validated by qRT-PCR in independent biological replicates of FACS-purified human fetal RGC.

Relative expression levels in the LG+Prlo subpopulation compared to LG+Prhi after normalization to housekeeping genes ACTB and GAPDH. Data represents six biological replicates (mean ± SEM) ranging from 16 WG to 23 WG (asterisk denotes p < 0.05, paired t-test; n=6, max p=0.045, all others were lower).

Supplementary Figure 4 Upregulation of proneural neurogenin targets in NEUROG2-VP16 electroporated ferret cells

In vivo delivery of GFP control and NEUROG2-VP16 constructs to ferret apical RGCs was performed by intraventricular injection and electroporation in neonatal ferret kits (n=2 per condition at postnatal day 1) as described in Figure 2. After 48 hours post-electroporation, electroporated cells were isolated for qRT-PCR analysis by enzymatic dissociation and FACS using their GFP fluorescence. Relative to GFP+ control electroporated cells, NEUROG2-VP16 expressing cells showed upregulation of many previously described NEUROG2 effector genes including Cbfa2t2, Foxn2, Foxp2, Hes6, Myt1, Neurod1, Neurod4, Neurog1, and Nhlh1, and down-regulation of Sox2. In addition, we also tested expression of ferret orthologs of human ORG-enriched genes and found that several including Gadd45g, Ttyh2, Sstr2, and Plcb4 were also upregulated in NEUROG2-VP16 cells compared to controls.

Supplementary Figure 5 Single-cell expression profiles of human and mouse RGC

a, Violin plots of RGC marker gene expression in human and mouse single sorted RGC reveals largely similar pattern of gene expression for RGC markers including SOX2, VIM, GLAST, BLBP, PAX6, NES. Interestingly, significant numbers of human RGC express GFAP and DCX but these genes are nearly absent in mouse RGC. b, Principle component analysis of 546 human (left) and 226 mouse (right) single RGC indicates distinct distributions of transcriptional states in human compared to mouse RGC. Here, “apical” is defined by expression of at least two of the four apical complex marker transcripts, and “proneural” by expression of at least two of the four Neurogenin pathway genes. In both species, the first PC (x-axis) reflects the proneural+/− dimension, with “multipotent” (presumptively pre-Neurogenin-pathway-expressing) RGC tending towards the left (red and blue cells) and proneural RGC on the right (black and green cells). Human cortex contains a greater proportion of proneural RGC, whereas mouse has fewer proneural cells which are less distinct, as indicated by the greater overlap of black and red cells in the mouse. In addition, human cortex displays far more non-apical (blue and green) cells than mouse, which again are more distinct from the apical (red and black) cells along the second PC (y-axis). In contrast, mouse non-apical RGC (blue and green) are scarce and not transcriptionally distinct from apical cells, as indicated by the lack of separation along the y-axis.

Supplementary Figure 6 Differential expression of novel unannotated lncRNAs in human RGC subtypes

RNA-seq reads displayed in genomic context for the LG+Prhi apical RGC (red), LG+Prlo ORG (green), and LG−Pr− cells (black). Novel transcripts assembled from the RNA-seq data are shown in blue, and previously catalogued lncRNA transcripts are shown in brown39. a, Two intergenic lncRNAs on chromosome 2 with distinct expression patterns in the human fetal cortex share a bidirectional promoter and overlap at their 5′ ends. The plus-strand lncRNA is enriched in apical RGC, whereas the minus-strand lncRNA is relatively enriched in ORG and neurons. Blue boxed region highlights the overlapping transcription start sites (TSS), and is enlarged below. Black arrows indicate read peaks from each strand's TSS. Bottom part of (a) shows the promoter at higher magnification, with expression levels of the two lncRNAs (in FPKM) plotted at right. b, Example of an ORG-enriched lncRNA. Multiple alternatively spliced isoforms of this multi-exon locus are expressed in all cell types assayed, but are significantly enriched in the LG+Prlo non-apical subpopulation. A partial transcript overlapping the 5′ end of the locus was previously detected by ultra-high depth RNA sequencing39; our data demonstrate that even low-abundance transcripts can be captured and fully reconstructed from an order of magnitude fewer reads when RNA is sequenced from the specific cell types that express the gene, rather than from heterogeneous bulk tissue. c, Example of a novel apical RGC-specific intergenic transcript not detected by previous deep-sequencing experiments.

Supplementary Figure 7 Differential enrichment of lncRNAs in human and mouse RGC populations

We performed qRT-PCR of several conserved lncRNAs in FACS-purified human (n=4 biological replicates ranging from 16 WG to 23 WG) and mouse RGC populations (n=3 from E15.5) comparing human ORG (LG+Prlo) and apical RGC (LG+Prhi) with neurons (LG−Pr−) and mouse RGC (L+Pr+) with neurons (L−Pr−) (mean ± SEM). We find that several conserved lncRNAs including LINC-PINT, TUNAR, CRNDE, MIR22HG are enriched in human RGC progenitor populations but depleted in mouse RGC suggesting potentially divergent roles in human radial progenitor evolution and function.

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Johnson, M., Wang, P., Atabay, K. et al. Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex. Nat Neurosci 18, 637–646 (2015). https://doi.org/10.1038/nn.3980

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