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Publication : Failure of human rhombic lip differentiation underlies medulloblastoma formation.

First Author  Hendrikse LD Year  2022
Journal  Nature Volume  609
Issue  7929 Pages  1021-1028
PubMed ID  36131014 Mgi Jnum  J:340417
Mgi Id  MGI:7525146 Doi  10.1038/s41586-022-05215-w
Citation  Hendrikse LD, et al. (2022) Failure of human rhombic lip differentiation underlies medulloblastoma formation. Nature 609(7929):1021-1028
abstractText  Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain(1-4). Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage(5-8). By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL(9,10). However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage(3,4). Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES(+)KI67(+) unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.
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