mDia formins form hetero-oligomers and cooperatively maintain murine hematopoiesis.
mDia formins form hetero-oligomers and cooperatively maintain murine hematopoiesis.
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MDIA formins形成异卵形物并合作维持鼠造血。
DOI：
10.1371/journal.pgen.1011084
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发表时间：
2023-12
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
媒质双胍蛋白通过其线性肌动蛋白成核和聚合活性调节细胞骨架的动力学和组织。我们之前在小鼠模型中表明，mDia1缺乏会导致异常先天免疫激活并诱导骨髓增生异常，而mDia2调节红细胞的去核和细胞分裂以及造血干细胞和祖细胞（HSPCs）的植入。然而，在生理和应激条件下，媒质形成蛋白是否以及如何相互作用和调节造血仍是未知的。在这里，我们发现mDia1和mDia2都是HSPC在应力下再生所必需的，比如连续电镀、老化和髓细胞消融后的重建。我们发现mDia1和mDia2通过mDia1 GBD-DID和mDia2 DAD结构域之间的相互作用形成异聚物。双敲除造血细胞中的mDia1和mDia2可协同破坏丝状肌动蛋白网络和血清反应因子相关的转录信号，从而导致新生儿和新生小鼠HSPCs下降、严重贫血和显著死亡率。我们的数据证明了培养基异寡聚化及其在调节造血干细胞活性和造血协调中的非啮齿动物功能的潜在作用。血液的产生和生成完全依赖于必须严格控制的造血干细胞（HSPCs）。中甲双胍蛋白是线状肌动蛋白合成的关键调节因子，参与肌动蛋白丝的形成和细胞骨架的组织。先前的研究已经揭示了mDia1或mDia2在调节T细胞、中性粒细胞或红细胞功能中的重要作用，但缺乏证据表明这两个因子在体内的非冗余作用。在这里，我们将mDia1和mDia2双缺陷小鼠的遗传操作与生化分析相结合。我们发现在体外和体内mDia1直接与mDia2相互作用形成异聚物，并且mDia1和mDia2都是维持小鼠应激时HSPCs止血所必需的。小鼠中mDia1和mDia2的双重缺乏导致血清反应因子（SRF）信号通路受损，HSPC下降，严重贫血，动物死亡率增加。我们的工作不仅为mDia1-mDia2复合体提供了一个以前未被认识的工作模型，而且强调了它们在造血中的协同作用。
mDia formin proteins regulate the dynamics and organization of the cytoskeleton through their linear actin nucleation and polymerization activities. We previously showed that mDia1 deficiency leads to aberrant innate immune activation and induces myelodysplasia in a mouse model, and mDia2 regulates enucleation and cytokinesis of erythroblasts and the engraftment of hematopoietic stem and progenitor cells (HSPCs). However, whether and how mDia formins interplay and regulate hematopoiesis under physiological and stress conditions remains unknown. Here, we found that both mDia1 and mDia2 are required for HSPC regeneration under stress, such as serial plating, aging, and reconstitution after myeloid ablation. We showed that mDia1 and mDia2 form hetero-oligomers through the interactions between mDia1 GBD-DID and mDia2 DAD domains. Double knockout of mDia1 and mDia2 in hematopoietic cells synergistically impaired the filamentous actin network and serum response factor-involved transcriptional signaling, which led to declined HSPCs, severe anemia, and significant mortality in neonates and newborn mice. Our data demonstrate the potential roles of mDia hetero-oligomerization and their non-rodent functions in the regulation of HSPCs activity and orchestration of hematopoiesis. Blood production and generation entirely depend on the hematopoietic stem progenitor cells (HSPCs) that have to be tightly controlled. mDia formin proteins are critical regulators for linear-actin synthesis that are involved in actin filament formation and cytoskeleton organization. Previous studies have revealed the important roles of mDia1 or mDia2 in regulating the functions of T cells, neutrophils, or red blood cells, but there is a lack of evidence for the non-redundant roles of these two factors in vivo. Here we combined genetic manipulation of the mDia1 and mDia2 double deficient mouse with biochemical analysis. We find that mDia1 interacts directly with mDia2 to form hetero-oligomers in vitro and in vivo, and both mDia1 and mDia2 are required to maintain HSPCs hemostasis during stress in mice. Dual deficiency of mDia1 and mDia2 in mice leads to compromised serum response factor (SRF) signaling, with declined HSPC, severe anemia, and increased animal mortality. Our work not only provides a previously unrecognized working model for the mDia1-mDia2 complex but also highlights their cooperative roles in hematopoiesis.
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影响因子：
5.8
作者：
Liu C;Zhu R;Mao Y
通讯作者：
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影响因子：
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通讯作者：
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影响因子：
16.6
作者：
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通讯作者：
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影响因子：
10.1
作者：
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通讯作者：
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