Childhood cerebellar tumours mirror conserved fetal transcriptional programs

Vladoiu, Maria C.; El-Hamamy, Ibrahim; Donovan, Laura; Farooq, Hamza; Holgado, Borja L.; Sundaravadanam, Yogi; Ramaswamy, Vijay; Hendrikse, Liam D.; Kumar, Sachin; Mack, Stephen C.; Lee, John J.Y.; Fong, Vernon; Juraschka, Kyle; Przelicki, David; Michealraj, Antony; Skowron, Patryk; Luu, Betty; Suzuki, Hiromichi; Morrissy, A. Sorana; Cavalli, Florence M.G.; Garzia, Livia; Daniels, Craig; Wu, Xiaochong; Qazi, Maleeha; Singh, Sheila K.; Chan, Jennifer A.; Marra, Marco A.; Malkin, David; Dirks, Peter B.; Heisler, Lawrence E.; Pugh, Trevor J.; Ng, Karen; Notta, Faiyaz; Thompson, Eric M.; Kleinman, Claudia L.; Joyner, Alexandra L.; Jabado, Nada; Stein, Lincoln; Taylor, Michael D.

doi:10.1038/s41586-019-1158-7

Cited by 306 publications

(410 citation statements)

References 55 publications

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“…Atoh1 + RL progenitors give rise to glutamatergic neurons, while Ptf1a + VZ progenitors give rise to GABAergic neurons 6 . However, pseudo-time trajectory analysis of single-cell RNAseq (scRNAseq) embryonic mouse cerebellum data suggests that a common pool of progenitors branches into either a glutamatergic fate or a GABAergic fate 7 . In addition, cell fate in the two germinal niches can be switched when Atoh1 and Ptf1a are ectopically expressed in the VZ and RL, respectively 8,9 .…”

Section: Body Textmentioning

confidence: 99%

Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum

Zhang

Liu

Mora

et al. 2020

Preprint

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14The bewildering diversity of brain neurons arises from relatively few pluripotent progenitors 15 through poorly understood mechanisms. The cerebellum is an attractive model to investigate 16 mechanisms of neuronal diversification because the different subtypes of excitatory and 17 inhibitory neurons are well described 1,2 . The cerebellum is a hub for control of motor function 18 and contributes to a number of higher brain functions such as reward-related cognitive 19 processes 3 . Deficits in cerebellar development lead to severe neurological disorders such as 20 cerebellar ataxias 4 and medulloblastomas 5 , a heterogeneous and severe groups of childhood 21 brain tumors, thus underlying the importance of understanding the cellular and molecular 22 control of cerebellar development. In contrast to text book models, we report that excitatory 23 and inhibitory cerebellar neurons derive from the same pluripotent embryonic cerebellar stem 24 cells (eCSC). We find that the excitatory versus inhibitory fate decision of a progenitor is 25 regulated by Notch signaling, whereby the cell with lower Notch activity adopts the excitatory 26 fate, while the cell with higher Notch activity adopts the inhibitory fate. Thus, Notch-mediated 27 binary cell fate choice is a conserved strategy for generating neuronal diversity from common 28 progenitors that is deployed at different developmental time points in a context specific manner. 29 30 31 Body text 32 Cerebellar anlagen 33 Text book models suggest that different cerebellar neurons arise from two distinct progenitor 34 pools (Fig.S1A) located either dorsally in the rhombic lip (RL) or ventrally in the ventricular 35 zone (VZ). Two basic helix-loop-helix (bHLH) transcription factors called Atonal homologue 36 1 (Atoh1; RL) and Pancreas transcription factor 1 alpha (Ptf1a; VZ), mark these progenitors. 37 Atoh1 + RL progenitors give rise to glutamatergic neurons, while Ptf1a + VZ progenitors give 38 rise to GABAergic neurons 6 . However, pseudo-time trajectory analysis of single-cell RNAseq 39 (scRNAseq) embryonic mouse cerebellum data suggests that a common pool of progenitors 40 branches into either a glutamatergic fate or a GABAergic fate 7 . In addition, cell fate in the two 41 germinal niches can be switched when Atoh1 and Ptf1a are ectopically expressed in the VZ 42 and RL, respectively 8,9 . Finally, the classic neural stem cell marker Sox2 is an early VZ marker, 43 but cells expressing both Sox2 and the RL marker Atoh1 were observed in human cerebellar 44 organoids 10 . Whether this means that common pluripotent progenitors competent to generate 45 both excitatory and inhibitory lineages exist, and how this binary fate decision is regulated, are 46 unknown. 47 52 Sox2 CreERT2 /Gt(ROSA)26Sor tdTomato /Atoh1 GFP mice using low doses of Tamoxifen (TM: 0.1mg, 53 0.03mg). Under both conditions, in all mice examined, Sox2 + cells and their progeny labelled 54 with tdTomato (tdTomato+). We observed Ptf1a + /tdTomato + and Atoh1 + /tdTomato + cells at 55 E12.5 in the VZ a...

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Section: Body Textmentioning

confidence: 99%

Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum

Zhang

Liu

Mora

et al. 2020

Preprint

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“…We first determined whether Bcor is normally expressed in developing cerebellar GNPs in mice, the cellof-origin for SHH-medulloblastoma (Yang et al 2008;Schüller et al 2008;Hovestadt et al 2019;Vladoiu et al 2019). Using RNA in situ hybridization (ISH), we found that Bcor is expressed in the outer external granule layer the C-terminal PUFD domain is inferred to be absent because of the introduction of premature STOP codons in 6/7 cases (Table 1).…”

Section: Bcor Is Expressed In Proliferating Granule Neuron Progenitormentioning

confidence: 99%

Functional loss of a non-canonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation

Kutscher

Okonechnikov

Batora

et al. 2020

Preprint

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Medulloblastoma is a childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH)-subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs) and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional co-repressor BCOR are recurrent and highly enriched in SHH-medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a germline genetically engineered mouse model to delete exons 9/10 of Bcor (BcorΔE9-10) in GNPs during development. This leads to reduced expression of C-terminally truncated BCOR (BCORΔE9-10). While BcorΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, BcorΔE9-10 combined with loss of the SHH-receptor gene Ptch1 resulted in highly penetrant medulloblastomas. In Ptch1+/-;BcorΔE9-10 tumors, the growth factor gene Igf2 was aberrantly upregulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1+/- GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1+/-;BcorΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.

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“…To distinguish group 3 and group 4, a similar 60%-40% training-tuning model was adapted for classification. 8 A random forest-based model for PCGs distinguishing WNT, SHH, group 3, and group 4 was obtained as described above for lncRNAs. To validate the protein coding model, expression levels of the obtained signature genes were used to classify patient samples from the MAGIC dataset using the random forest model and tSNE plots.…”

Section: Random Forest Modelmentioning

confidence: 99%

“…, characterized as WHO group IV, represents the most common malignant pediatric central nervous system (CNS) tumor [1][2][3][4], representing 9.2% of all pediatric brain tumor cases [1,5] and roughly 500 new cases each year in the US. MBs originate in the cerebellum and share molecular signatures with embryonic cerebellar lineages, with metastasis sites commonly include parts of the brain, spinal cord, and, rarely, to extraneural sites [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

In silico analysis of long non-coding RNAs in medulloblastoma and its subgroups

Joshi

Perera

2019

Preprint

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AbstractMedulloblastoma is the most common malignant pediatric brain tumor with high fatality rate. Recent large-scale studies utilizing genome-wide technologies have sub-grouped medulloblastomas into four major subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. However, there has yet to be a global analysis of long non-coding RNAs, a crucial part of the regulatory transcriptome, in medulloblastoma. Here, we performed bioinformatic analysis of RNA-seq data from 175 medulloblastoma patients. Differential lncRNA expression sub-grouped medulloblastomas into the four main molecular subgroups. Some of these lncRNAs were subgroup-specific, with a random forest-based machine-learning algorithm identifying an 11-lncRNA diagnostic signature. We also validated the diagnostic signature in patient derived xenograft (PDX) models. We further identified a 17-lncRNA prognostic model using LASSO based penalized Cox’ PH model (Score HR= 13.6301, 95% CI= 8.857-20.98, logrank p-value=< 2e-16). Our analysis represents the first global lncRNA analysis in medulloblastoma. Our results identify putative candidate lncRNAs that could be evaluated for their functional role in medulloblastoma genesis and progression or as diagnostic and prognostic biomarkers.

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Childhood cerebellar tumours mirror conserved fetal transcriptional programs

Cited by 306 publications

References 55 publications

Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum

Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum

Functional loss of a non-canonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation

In silico analysis of long non-coding RNAs in medulloblastoma and its subgroups

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