We previously described two donors in whom the extracellular domain of LAIR1, a collagenbinding inhibitory receptor encoded on chromosome 191, was inserted between the V and the DJ segments of an antibody. This insertion generated, through somatic mutations, broadly reactive antibodies against RIFINs, a type of variant antigen expressed on the surface of Plasmodium falciparum-infected erythrocytes (IEs)2. To investigate how frequently such antibodies are produced in response to malaria infection, we screened plasma from two large cohorts of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

Medulloblastoma (MB) is the most common malignant brain tumor in children and among the subtypes, Group 3 MB has the worst outcome. Here, we perform an in vivo, patientspecific screen leading to the identification of Otx2 and c-MYC as strong Group 3 MB inducers. We validated our findings in human cerebellar organoids where Otx2/c-MYC give rise to MB-like organoids harboring a DNA methylation signature that clusters with human Group 3 tumors. Furthermore, we show that SMARCA4 is able to reduce Otx2/c-MYC tumorigenic activity in vivo and in human cerebellar organoids while SMARCA4 T910M, a mutant form found in human MB patients, inhibits the wild-type protein function. Finally, treatment with Tazemetostat, a EZH2-specific inhibitor, reduces Otx2/c-MYC tumorigenesis in ex vivo culture and human cerebellar organoids. In conclusion, human cerebellar organoids can be efficiently used to understand the role of genes found altered in cancer patients and represent a reliable tool for developing personalized therapies.

Highlights d GABAergic and glutamatergic cerebellar neurons are generated from Sox2 + progenitors d Single Sox2 + ECPs can give rise to both excitatory and inhibitory cerebellar neurons d Notch activity mediates GABAergic versus glutamatergic cell fates in Sox2 + ECPs

Graphical Abstract Highlights d SmoM2 overexpression promotes cerebellar granule neurons dedifferentiation in vivo d SmoM2 and mutant BRPF1 cooperation in vivo mimics human adult SHH MBs d Granule neurons are putative cells of origin of adult SHH MBs d Truncated BRPF1 increases the accessibility of a subset of super-enhancers In Brief Medulloblastoma is a brain tumor affecting the cerebellum of infants and adults. Aiello et al. establish a mouse model for adult onset, which allows investigation of the pathogenesis of the disease and identifies neurons as putative cells of origin.

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...

The identity of the cell of origin is a key determinant of cancer subtype, progression, and prognosis. Group 3 medulloblastoma (MB) is a malignant childhood brain cancer with poor prognosis and few candidates as putative cell of origin. We overexpressed the group 3 MB genetic drivers MYC and Gfi1 in different candidate cells of origin in the postnatal mouse cerebellum. We found that S100b+ cells are competent to initiate group 3 MB, and we observed that S100b+ cells have higher levels of Notch1 pathway activity compared to Math1+ cells. We found that additional activation of Notch1 in Math1+ and Sox2+ cells was sufficient to induce group 3 MB upon MYC/Gfi1 expression. Together, our data suggest that the Notch1 pathway plays a critical role in group 3 MB initiation.

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