PRC2 disruption in cerebellar progenitors produces cerebellar hypoplasia and aberrant myoid differentiation without blocking medulloblastoma growth

• Published in: Acta neuropathologica communications Vol. 11; no. 1; p. 8
• Main Authors: Cleveland, Abigail H, Malawsky, Daniel, Churiwal, Mehal, Rodriguez, Claudia, Reed, Frances, Schniederjan, Matthew, Velazquez Vega, Jose E, Davis, Ian, Gershon, Timothy R
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 12-01-2023; BioMed Central; BMC
• Subjects: Analysis; Brain; Cell Differentiation; Cell Proliferation; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - metabolism; Cerebellum - metabolism; Epigenetic inheritance; Fate commitment; Growth; H3K27me3; Health aspects; Humans; Medulloblastoma; Medulloblastoma - genetics; Medulloblastoma - metabolism; Medullomyoblastoma; Neurons; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; PRC2; Proteins; Fate commitment; PRC2; Medullomyoblastoma; H3K27me3
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-023-01508-x

We show that Polycomb Repressive Complex-2 (PRC2) components EED and EZH2 maintain neural identity in cerebellar granule neuron progenitors (CGNPs) and SHH-driven medulloblastoma, a cancer of CGNPs. Proliferating CGNPs and medulloblastoma cells inherit neural fate commitment through epigenetic mechanisms. The PRC2 is an epigenetic regulator that has been proposed as a therapeutic target in medulloblastoma. To define PRC2 function in cerebellar development and medulloblastoma, we conditionally deleted PRC2 components Eed or Ezh2 in CGNPs and analyzed medulloblastomas induced in Eed-deleted and Ezh2-deleted CGNPs by expressing SmoM2, an oncogenic allele of Smo. Eed deletion destabilized the PRC2, depleting EED and EZH2 proteins, while Ezh2 deletion did not deplete EED. Eed-deleted cerebella were hypoplastic, with reduced proliferation, increased apoptosis, and inappropriate muscle-like differentiation. Ezh2-deleted cerebella showed similar, milder phenotypes, with fewer muscle-like cells and without reduced growth. Eed-deleted and Ezh2-deleted medulloblastomas both demonstrated myoid differentiation and progressed more rapidly than PRC2-intact controls. The PRC2 thus maintains neural commitment in CGNPs and medulloblastoma, but is not required for SHH medulloblastoma progression. Our data define a role for the PRC2 in preventing inappropriate, non-neural fates during postnatal neurogenesis, and caution that targeting the PRC2 in SHH medulloblastoma may not produce durable therapeutic effects.