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

Authors :
Abigail H. Cleveland
Daniel Malawsky
Mehal Churiwal
Claudia Rodriguez
Frances Reed
Matthew Schniederjan
Jose E. Velazquez Vega
Ian Davis
Timothy R. Gershon
Source :
Acta Neuropathologica Communications, Vol 11, Iss 1, Pp 1-19 (2023)
Publication Year :
2023
Publisher :
BMC, 2023.

Abstract

Abstract 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.

Details

Language :
English
ISSN :
20515960
Volume :
11
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Acta Neuropathologica Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.95e9bb36f24f898a4974b26fb6a823
Document Type :
article
Full Text :
https://doi.org/10.1186/s40478-023-01508-x