Myeloproliferative defects following targeting of the Drf1 gene encoding the mammalian diaphanous-related formin mDia1
Myeloproliferative defects following targeting of the Drf1 gene encoding the mammalian diaphanous-related formin mDia1
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DOI：
10.1158/0008-5472.can-07-1467
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发表时间：
2007-08-15
期刊：
影响因子：
11.2
通讯作者：
Alberts, Arthur S.
中科院分区：
文献类型：
--
作者：
Peng, Jun;Kitchen, Susan M.;Alberts, Arthur S.
Rho GTP酶效应哺乳动物透明（mDia）相关的formin组装非分支肌动蛋白丝作为细胞过程的一部分，包括细胞分裂，丝状伪足组装和细胞内运输。虽然最近的努力已经导致彻底的表征formins在细胞骨架重塑和肌动蛋白组装在体外，很少有人知道的mDia蛋白在体内的作用。为了填补这一知识空白，通过同源重组靶向了编码典型的DermDial的Drf 1基因。出生后，Drf 1（+/-）和Drf 1（-/-）小鼠在发育和形态学上与其野生型同窝小鼠无区别。然而，Drf 1（+/-）和Drf 1（-/-）均出现年龄依赖性骨髓增殖缺陷。表型包括脾肿大、骨髓纤维化和细胞过多、脾和肝中的髓外造血以及存在具有高核质比的未成熟骨髓祖细胞。细胞表面标志物分析显示，在Drf 1（+/-）和Drf 1（-/-）动物中，脾脏和骨髓中CD 11b（+）活化和CD 14（+）活化单核细胞/巨噬细胞的百分比呈年龄依赖性增加。红系细胞区室分析显示，在Drf 1靶向小鼠中，S期脾细胞比例显著增加，红系前体细胞（TER-119（+）和CD 71（+））扩增。总之，敲除小鼠中的mDial表达导致与人骨髓增生综合征（MPS）和骨髓增生异常综合征（MDS）相似的表型。这些观察结果表明，缺陷的DRF 1表达或mDial功能可能有助于骨髓恶性肿瘤，并指出mDial作为MDS和MPS中有吸引力的治疗靶点。
Rho GTPase-effector mammalian diaphanous (mDia)-related formins assemble nonbranched actin filaments as part of cellular processes, including cell division, filopodia assembly, and intracellular trafficking. Whereas recent efforts have led to thorough characterization of formins in cytoskeletal remodeling and actin assembly in vitro, little is known about the role of mDia proteins in vivo. To fill this knowledge gap, the Drf1 gene, which encodes the canonical formin mDial, was targeted by homologous recombination. Upon birth, Drf1(+/-) and Drf1(-/-) mice were developmentally and morphologically indistinguishable from their wild-type littermates. However, both Drf1(+/-) and Drf1(-/-) developed age-dependent myeloproliferative defects. The phenotype included splenomegaly, fibrotic and hypercellular bone marrow, extramedullary hematopoiesis in both spleen and liver, and the presence of immature myeloid progenitor cells with high nucleus-to-cytoplasm ratios. Analysis of cell surface markers showed an age-dependent increase in the percentage of CD11b(+)-activated and CD14(+)-activated monocytes/macrophages in both spleen and bone marrow in Drf1(+/-) and Drf1(-/-) animals. Analysis of the erythroid compartment showed a significant increase in the proportion of splenic cells in S phase and an expansion of erythroid precursors (TER-119(+) and CD71(+)) in Drf1-targeted mice. Overall, knocking out mDial expression in mice leads to a phenotype similar to human myeloproliferative syndrome (MPS) and myelodysplastic syndromes (MDS). These observations suggest that defective DRF1 expression or mDial function may contribute to myeloid malignancies and point to mDial as an attractive therapeutic target in MDS and MPS.