PRC2 disruption in cerebellar progenitors produces cerebellar hypoplasia and aberrant myoid differentiation without blocking medulloblastoma growth.
PRC2 disruption in cerebellar progenitors produces cerebellar hypoplasia and aberrant myoid differentiation without blocking medulloblastoma growth.
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DOI：
10.1186/s40478-023-01508-x
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发表时间：
2023-01-12
影响因子：
7.1
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中科院分区：
文献类型：
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我们发现多梳抑制复合体-2 （PRC2）成分EED和EZH2在小脑颗粒神经元祖细胞（CGNPs）和shh驱动的髓母细胞瘤（CGNPs的一种癌症）中维持神经身份。增殖的CGNPs和成神经管细胞瘤细胞通过表观遗传机制继承神经命运承诺。PRC2是一种表观遗传调控因子，已被提出作为髓母细胞瘤的治疗靶点。为了明确PRC2在小脑发育和成神经管细胞瘤中的功能，我们在CGNPs中有条件地删除了PRC2成分Eed或Ezh2，并通过表达Smo的致癌等位基因SmoM2来分析ed缺失和Ezh2缺失的CGNPs诱导的成神经管细胞瘤。Eed的缺失破坏了PRC2的稳定性，减少了Eed和EZH2蛋白，而EZH2的缺失没有减少Eed。ed缺失的小脑发育不良，增生减少，细胞凋亡增加，不适当的肌肉样分化。ezh2缺失的小脑表现出类似的、温和的表型，具有更少的肌肉样细胞，并且没有减少生长。ed-缺失和ezh2缺失的髓母细胞瘤均表现出肌样分化，并且比prc2完整的对照组进展更快。因此，PRC2在CGNPs和成神经管细胞瘤中维持神经功能，但在SHH成神经管细胞瘤的进展中不是必需的。我们的数据确定了PRC2在预防出生后神经发生过程中不适当的非神经命运中的作用，并警告在SHH成神经管细胞瘤中靶向PRC2可能不会产生持久的治疗效果。在线版本包含补充材料，可在10.1186/s40478-023-01508-x获得。
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. The online version contains supplementary material available at 10.1186/s40478-023-01508-x.
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影响因子：
13.6
作者：
Lim C;Dismuke T;Malawsky D;Ramsey JD;Hwang D;Godfrey VL;Kabanov AV;Gershon TR;Sokolsky-Papkov M
通讯作者：
Sokolsky-Papkov M
影响因子：
5.7
作者：
Guo, Jianfeng;Cai, Jing;Wang, Zehua
通讯作者：
Wang, Zehua
影响因子：
29.4
作者：
Koppens, Martijn A. J.;Bounova, Gergana;van Lohuizen, Maarten
通讯作者：
van Lohuizen, Maarten
影响因子：
4.6
作者：
Feng, Xuesong;Juan, Aster H.;Sartorelli, Vittorio
通讯作者：
Sartorelli, Vittorio
影响因子：
4.6
作者：
Lang, Patrick Y.;Nanjangud, Gouri J.;Gershon, Timothy R.
通讯作者：
Gershon, Timothy R.