The Friend of GATA Transcriptional Co-Regulator, U-Shaped, Is a Downstream Antagonist of Dorsal-Driven Prohemocyte Differentiation in Drosophila.
The Friend of GATA Transcriptional Co-Regulator, U-Shaped, Is a Downstream Antagonist of Dorsal-Driven Prohemocyte Differentiation in Drosophila.
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DOI：
10.1371/journal.pone.0155372
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Fossett N
中科院分区：
文献类型：
--
作者：
Gao H;Baldeosingh R;Wu X;Fossett N
最近的研究表明，哺乳动物造血干细胞和祖细胞（HSPCs）直接响应感染和炎症信号。这些信号通路还在稳态条件下（不存在感染）调节HSPC，并且失调可能导致癌症或与年龄相关的祖细胞再增殖能力丧失。Toll样受体（TLR）是一类主要的病原体识别受体，表达于免疫效应细胞和HSPC的表面。TLR/NF-κB激活促进HSPCs分化;然而，该信号通路改变内在转录景观的机制尚不清楚。虽然果蝇原血细胞是哺乳动物HSPC的功能等价物，但Toll信号传导的原血细胞特异性功能尚未报道。使用果蝇转基因，我们确定了Toll通路成员，背和仙人掌的prohemocyte-specific角色。我们发现，Dorsal是限制祖细胞库大小所必需的。此外，我们发现，原血细胞中Toll信号的激活以类似于TLR/NF-κ B驱动的HSPC分化的方式驱动分化。这是通过显示Dorsal的过表达或Cactus的敲低促进分化来实现的。我们还研究了Dorsal和Cactus是否通过调节关键的内在前血细胞因子U形（Ush）来控制前血细胞分化，该因子已知可促进多能性和阻断分化。我们发现Dorsal抑制Ush表达水平以促进分化，而Cactus维持Ush水平以阻断分化。此外，我们发现另一种Toll拮抗剂Lesswright也维持了Ush的水平，以阻断分化并促进增殖静止。总的来说，这些结果确定了Ush作为Toll信号传导的下游靶点的新作用。
Recent studies suggest that mammalian hematopoietic stem and progenitor cells (HSPCs) respond directly to infection and inflammatory signaling. These signaling pathways also regulate HSPCs during steady-state conditions (absence of infection), and dysregulation may lead to cancer or age-related loss of progenitor repopulation capacity. Toll-like receptors (TLRs) are a major class of pathogen recognition receptors, and are expressed on the surface of immune effector cells and HSPCs. TLR/NF-κB activation promotes HSPCs differentiation; however, the mechanisms by which this signaling pathway alters the intrinsic transcriptional landscape are not well understood. Although Drosophila prohemocytes are the functional equivalent of mammalian HSPCs, a prohemocyte-specific function for Toll signaling has not been reported. Using Drosophila transgenics, we identified prohemocyte-specific roles for Toll pathway members, Dorsal and Cactus. We showed that Dorsal is required to limit the size of the progenitor pool. Additionally, we showed that activation of Toll signaling in prohemocytes drives differentiation in a manner that is analogous to TLR/NF-κB-driven HSPC differentiation. This was accomplished by showing that over-expression of Dorsal, or knockdown of Cactus, promotes differentiation. We also investigated whether Dorsal and Cactus control prohemocyte differentiation by regulating a key intrinsic prohemocyte factor, U-shaped (Ush), which is known to promote multipotency and block differentiation. We showed that Dorsal repressed Ush expression levels to promote differentiation, whereas Cactus maintained Ush levels to block differentiation. Additionally, we showed that another Toll antagonist, Lesswright, also maintained the level of Ush to block differentiation and promote proliferative quiescence. Collectively, these results identify a novel role for Ush as a downstream target of Toll signaling.