Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comment
. 2025 Jul;643(8071):E1-E8.
doi: 10.1038/s41586-025-09247-w. Epub 2025 Jul 9.

Lack of evidence for the transitional cerebellar progenitor

Kyle S Smith #  1   2 , Yiran Li #  1   2 , Parthiv Haldipur  3 , Brian L Gudenas  1   2 , Kathleen J Millen  3 , Volker Hovestadt  4 , Paul A Northcott  5   6
Affiliations
Comment

Lack of evidence for the transitional cerebellar progenitor

Kyle S Smith et al. Nature. 2025 Jul.
No abstract available

PubMed Disclaimer

Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

Extended Data Figure 1.
Extended Data Figure 1.. Transcriptomic quality control of TCP cells.
(a,b) UMAP plots of the reanalyzed Luo study human cerebellar dataset, including all cells (a) and isolated neuronal cell types (b). (c,d) UMAP plots of PCW13 and PCW14 samples indicating cell type composition, predicted background fraction, and droplet efficiency with TCP cells outlined in red. (e) Predicted nuclear fraction and log10 UMI counts per sample (PCW8-17) with TCP cells indicated in black. Empty droplets are highlighted in orange and the damaged cell prediction threshold is shown as determined by DropletQC. (f,g) UMAP plots of the reanalyzed cerebellar dataset after removing TCP cells from the PCW12 sample with remaining TCP cells outlined in red (f) and colored by unsupervised clustering analysis (g).
Extended Data Figure 2.
Extended Data Figure 2.. Biases associated with differential expression of proposed TCP marker genes.
(a) Scatter plot showing the proportion of NSC cells expressing individual genes compared to non-NSC cells with exemplary marker genes highlighted in red. (b) Volcano plot of differentially expressed genes in NSC versus non-NSC cells from the complete Luo study cerebellar atlas (two-sided Wilcoxon rank sum test). (c) Volcano plot of differentially expressed genes in TCP versus non-TCP cells (two-sided Wilcoxon rank sum test). (d) UMAP plots of all annotated TCP cells colored by sample and showing normalized gene expression of proposed TCP marker genes. (e) Volcano plots of differentially expressed genes in TCP versus non-TCP cells using (two-sided Wilcoxon rank sum test) for PCW12, PCW13, and PCW14 samples.
Figure 1.
Figure 1.. TCP cells are consistent with low-quality cells.
(a-c) UMAP plots summarizing the Luo study fetal human cerebellar atlas by (a) cell type, (b) TCP distribution, and (c) sample. (d) Number of UMI counts and genes per cell in each cell type. Boxes represent the first, median, and third quartiles, with whiskers extending to 1.5× the interquartile range. (e) Number of UMI counts in TCP and non-TCP cells. Pie charts depict the proportion of TCP cells per sample. Boxes represent the first, median, and third quartiles, with whiskers extending to 1.5× the interquartile range; n = 95,542 cells over 8 independent donors. (f) Predicted background fraction and droplet efficiency in neuronal cell types from the reanalyzed PCW12 sample. (g) Scatter plot of nuclear fraction and log10 UMI counts per cell in the PCW12 and PCW13 samples.
Figure 2.
Figure 2.. Invariant expression of proposed TCP marker genes.
(a) Expression of marker genes by neuronal cell type as published in the Luo study. TCP marker genes indicated in red. (b) Scatter plot showing the proportion of TCP cells expressing individual genes (≥1 UMIs) compared to non-TCP cells. TCP marker genes indicated in red. (c) Volcano plot of differentially expressed genes in TCP versus non-TCP cells. TCP marker genes indicated in red. FDR corrected two-sided negative binomial general linear model test. (d) Heatmap showing mean prediction scores determined by PCA projection between cell types annotated in Luo and Sepp study cerebellar atlases. (e) Enrichment scores for TCP and NSC gene sets in respective cerebellar datasets. (f) RNAScope of SOX11 and HNRNPH1 in developing human cerebellum; scale bars indicate 500μm. (g) Cerebellar cell type proportions in MB subgroups as determined by CIBERSORTx (top) and MuSiC (bottom). (h) TCP marker gene expression in MB datasets. * = FDR corrected two-sided P-value=0.0313; *** = FDR corrected two-sided P-value<6.92x10−6; Empirical Bayes moderated t-test. Boxes represent the first, median, and third quartiles, with whiskers extending to 1.5× the interquartile range. (i) Density plot of gene effect for HNRNPH1 in DepMap.
See this image and copyright information in PMC

Comment on

References

Literature cited:

    1. Coorens THH and Behjati S, Tracing and Targeting the Origins of Childhood Cancer. Annual Review of Cancer Biology, 2022. 6(1): p. 35–47.
    1. Luo Z, et al. , Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis. Nature, 2022. 612(7941): p. 787–794. - PubMed
    1. Northcott PA, et al. , Medulloblastoma. Nat Rev Dis Primers, 2019. 5(1): p. 11. - PubMed
    1. Fleming SJ, et al. , Unsupervised removal of systematic background noise from droplet-based single-cell experiments using CellBender. Nat Methods, 2023. 20(9): p. 1323–1335. - PubMed
    1. Muskovic W and Powell JE, DropletQC: improved identification of empty droplets and damaged cells in single-cell RNA-seq data. Genome Biol, 2021. 22(1): p. 329. - PMC - PubMed

Methods cited:

    1. Wolf FA, Angerer P, and Theis FJ, SCANPY: large-scale single-cell gene expression data analysis. Genome Biol, 2018. 19(1): p. 15. - PMC - PubMed
    1. Hao Y, et al. , Integrated analysis of multimodal single-cell data. Cell, 2021. 184(13): p. 3573–3587 e29. - PMC - PubMed
    1. Steen CB, et al. , Profiling Cell Type Abundance and Expression in Bulk Tissues with CIBERSORTx. Methods Mol Biol, 2020. 2117: p. 135–157. - PMC - PubMed

LinkOut - more resources