The cell fate determinant Scribble is required for maintenance of hematopoietic stem cell function
The cell fate determinant Scribble is required for maintenance of hematopoietic stem cell function
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DOI：
10.1038/s41375-018-0025-0
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发表时间：
2018-05-01
期刊：
影响因子：
11.4
通讯作者：
Heide, Florian H.
中科院分区：
文献类型：
--
作者：
Mohr, Juliane;Dash, Banaja P.;Heide, Florian H.
细胞命运决定因子影响造血干细胞的自我更新潜能。Scribble和Llgl1属于Scribble极性复合物，在果蝇中具有肿瘤抑制功能。在造血细胞中，Llgll的遗传失活导致干细胞库的扩增并增加自我更新能力而不赋予恶性转化。在这里，我们表明，其假定的复杂的合作伙伴Scribble基因失活的造血干细胞（HSC）在连续移植和应激过程中的功能障碍的结果。尽管Scribble的缺失使参与干细胞增殖、细胞信号传导和细胞运动性的转录下游效应物失调，但这些效应物不与Llgl1的转录靶重叠。在造血细胞中使用亲和纯化，然后通过质谱分析的Scribble的结合伴侣分析证实了其在细胞信号传导和运动性中的作用，但不用于结合果蝇中描述的极性模块。最后，Scribble对自我更新能力的要求也影响白血病干细胞的功能。因此，Scribble是成体HSC的调节剂，在细胞应激阶段对HSC的维持至关重要。
Cell fate determinants influence self-renewal potential of hematopoietic stem cells. Scribble and Llgl1 belong to the Scribble polarity complex and reveal tumor-suppressor function in drosophila. In hematopoietic cells, genetic inactivation of Llgll leads to expansion of the stem cell pool and increases self-renewal capacity without conferring malignant transformation. Here we show that genetic inactivation of its putative complex partner Scribble results in functional impairment of hematopoietic stem cells (HSC) over serial transplantation and during stress. Although loss of Scribble deregulates transcriptional downstream effectors involved in stem cell proliferation, cell signaling, and cell motility, these effectors do not overlap with transcriptional targets of Llgl1. Binding partner analysis of Scribble in hematopoietic cells using affinity purification followed by mass spectometry confirms its role in cell signaling and motility but not for binding to polarity modules described in drosophila. Finally, requirement of Scribble for self-renewal capacity also affects leukemia stem cell function. Thus, Scribble is a regulator of adult HSCs, essential for maintenance of HSCs during phases of cell stress.