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在原性或树突系中表达ENL YEATS域瘤突变会损害脏发育

Zhaoyu Xue¹, Hongwen Xuan¹, Kin Lau²

¹Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503, USA.

Nature communications

|March 15, 2025

概括

在小鼠中,ENL蛋白中的功能获取突变会破坏脏发育. 这些突变会导致严重的血统特异性缺陷,影响形成并导致新生儿死亡,突出显示ENL.

科学领域:

发展生物学发展生物学
癌症生物学癌症生物学
遗传学是一个遗传学.

背景情况:

在ENL (内皮微管相关蛋白类1) 蛋白中出现反复的功能增益突变,在威尔姆斯瘤中发现,这是一种常见的儿科癌.
这些ENL突变在脏发育和体内癌症发病中的确切作用尚不清楚.

研究的目的:

用小鼠模型调查ENL瘤 (ENL^T) 突变在脏发育和瘤发生中的病理意义.
阐明ENL突变破坏特定细胞系内发生的独特机制.

主要方法:

产生表达异构性ENL^T突变的小鼠模型,在Six2-阳性 (nephrogenic) 和Foxd1-阳性 (stromal) 血统中.
突变脏的表型分析,包括组织学检查和发育缺陷的评估.
批量和空间转录组分析以确定突变细胞中的基因表达变化.

主要成果:

在Six2+神经细胞中异构性ENL^T表达导致严重的脏缺陷,包括受损的囊介质,减少脏形成和囊性球粒,具有异常的Hox和Wnt信号.
在Foxd1+ stromal细胞中,ENL^T表达导致囊和囊介质扩张和失调的 stromal 基因表达,损害了 stroma-epithelium 交叉.
这两种突变模型都导致了新生儿死亡率,这是由于不同的血统特异性脏异常造成的.

结论:

恩尔细胞突变通过特定的基因机制破坏了发育 (生) 所必需的独特途径.
这些发现提供了关于ENL突变如何导致脏形的关键见解,并为了解它们在威尔姆斯瘤发病过程中的作用提供了基础.

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