Dynamin 2-dependent endocytosis is required for normal megakaryocyte development in mice
Dynamin 2-dependent endocytosis is required for normal megakaryocyte development in mice
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DOI：
10.1182/blood-2014-07-587857
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发表时间：
2015-02-05
期刊：
影响因子：
20.3
通讯作者：
Falet, Herve
中科院分区：
文献类型：
--
作者：
Bender, Markus;Giannini, Silvia;Falet, Herve
动力蛋白是高度保守的大型gtp酶（水解鸟苷三磷酸的酶），参与内吞作用和囊泡运输，并且普遍存在的清洁动力蛋白2 （DNM2）的突变与人类血小板减少症有关。为了确定DNM2在血小板形成中的作用，我们在巨核细胞（MK）谱系中培养了特异性缺乏DNM2的DNM2 (fl/fl) Pf4-Cre小鼠。Dnm2(fl/fl) Pf4-Cre小鼠有严重的大血小板减少症，血小板清除中度加速。由于内吞途径的缺陷，dnm2缺失的骨髓MK在体内改变了分界膜系统的形成，而胎儿肝脏来源的dnm2缺失的MK在体外形成血小板的能力较差，表明dnm2依赖的内吞作用在MK膜的形成和血小板形成中起着重要作用。在无dnm2的血小板中，血小板生成素受体Mpl的内吞作用受损，导致酪氨酸激酶JAK2的构成性磷酸化和循环血小板生成素水平升高。MK特异性DNM2缺失严重破坏了骨髓稳态，这反映在造血干细胞和祖细胞的显著扩增、MK增生、骨髓纤维化以及随之而来的髓外造血和脾肿大上。综上所述，我们的数据表明，无限制的MK生长和增殖导致快速骨髓纤维化，并确立了dnm2依赖性内吞作用在巨核生成、血小板生成和骨髓稳态中的先前未被认识到的作用。
Dynamins are highly conserved large GTPases (enzymes that hydrolyze guanosine triphosphate) involved in endocytosis and vesicle transport, and mutations in the ubiquitous and housekeeping dynamin 2 (DNM2) have been associated with thrombocytopenia in humans. To determine the role of DNM2 in thrombopoiesis, we generated Dnm2(fl/fl) Pf4-Cre mice specifically lacking DNM2 in the megakaryocyte (MK) lineage. Dnm2(fl/fl) Pf4-Cre mice had severe macrothrombocytopenia with moderately accelerated platelet clearance. Dnm2-null bone marrow MKs had altered demarcation membrane system formation in vivo due to defective endocytic pathway, and fetal liver-derived Dnm2-null MKs formed proplatelets poorly in vitro, showing that DNM2-dependent endocytosis plays a major role in MK membrane formation and thrombopoiesis. Endocytosis of the thrombopoietin receptor Mpl was impaired in Dnm2-null platelets, causing constitutive phosphorylation of the tyrosine kinase JAK2 and elevated circulating thrombopoietin levels. MK-specific DNM2 deletion severely disrupted bone marrow homeostasis, as reflected by marked expansion of hematopoietic stem and progenitor cells, MK hyperplasia, myelofibrosis, and consequent extramedullary hematopoiesis and splenomegaly. Taken together, our data demonstrate that unrestrained MK growth and proliferation results in rapid myelofibrosis and establishes a previously unrecognized role for DNM2-dependent endocytosis in megakaryopoiesis, thrombopoiesis, and bone marrow homeostasis.