Dynamin-2 deficiency causes age- and sex-dependent neutropenia and myelodysplasia in mice.
Dynamin-2 deficiency causes age- and sex-dependent neutropenia and myelodysplasia in mice.
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DOI：
10.1182/bloodadvances.2022008135
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发表时间：
2023-04-25
期刊：
影响因子：
7.5
通讯作者：
Chen, Yolande
中科院分区：
文献类型：
--
作者：
Willis, Alexander J.;Corey, Seth J.;Murga-Zamalloa, Carlos;Karimi, Saman S.;Khaddour, Karam;Quigley, John;Eklund, Elizabeth A.;Chen, Yolande
Dynamin-2 单倍体缺陷雌性小鼠随着年龄的增长会出现中性粒细胞减少症。中性粒细胞减少症是由于骨髓生成障碍和迁移缺陷导致的产生缺陷造成的。动力蛋白是一个普遍表达的 GTP 酶蛋白家族，以其在膜重塑中的作用而闻名。它们对造血的贡献尚未得到完全认识。患有 dynamin-2 (DNM2) 突变的腓骨肌萎缩症患者通常会出现中性粒细胞减少症。我们之前报道过动力蛋白 (DNM) 抑制会损害 SDF1a 介导的巨核细胞迁移。在这里，我们使用 Vav-Cre 小鼠品系报告了造血组织中条件性 Dnm2 缺失的小鼠。血液组织中的纯合 Dnm2 缺失会导致胚胎死亡。 Dnm2het 雄性小鼠的血红蛋白水平仅略有下降。 Dnm2het 雌性小鼠在 40 周龄时出现白细胞减少症，在 65 周龄时出现中性粒细胞减少症。流式细胞术显示 Dnm2het 雌性小鼠中谱系阴性细胞和粒细胞-单核细胞祖细胞减少。 Ly6G 对骨髓 (BM) 的成熟中性粒细胞的免疫组织化学染色减少，并且 Dnm2het 雌性小鼠的 BM 中存在骨髓增生异常特征。与对照组相比，在较少的 Dnm2het 小鼠中观察到 Ly6G+ BM 细胞沿血管的线性分布，表明骨髓中的迁移模式发生了改变。用动力抑制剂 dynasore 处理的骨髓中性粒细胞显示细胞表面 CXCR4 增加，表明异常迁移导致骨髓中性粒细胞滞留。 Dnm2het 雌性小鼠在年轻时也会出现继发于生发中心增生的脾肿大，这表明免疫力受到干扰。总之，随着年龄的增长，BM Dnm2 单倍体不足的雌性小鼠会出现中性粒细胞减少症，并伴有粒细胞祖细胞生成减少和迁移缺陷。我们的研究表明了慢性特发性中性粒细胞减少症（一种主要出现在中年女性中的疾病）发展的潜在机制。
Dynamin-2 haplodeficient female mice develop neutropenia with aging. Neutropenia is because of defective production from dysmyelopoiesis and migration defects. The dynamins are a family of ubiquitously expressed GTPase proteins, best known for their role in membrane remodeling. Their contribution to hematopoiesis is incompletely recognized. Individuals with Charcot-Marie-Tooth disease with dynamin-2 (DNM2) mutations often develop neutropenia. We previously reported that dynamin (DNM) inhibition impairs SDF1a-mediated migration in megakaryocytes. Here, we report on conditionally Dnm2 deleted mice in hematopoietic tissues using the Vav-Cre murine strain. Homozygous Dnm2 deletion in blood tissues is embryonic lethal. Dnm2het male mice only developed a slightly decreased hemoglobin level. Dnm2het female mice developed leukopenia by 40 weeks of age and neutropenia by 65 weeks of age. Flow cytometry revealed decreased lineage-negative cells and granulocyte-monocyte progenitors in Dnm2het female mice. Immunohistochemical staining of bone marrow (BM) for mature neutrophils with Ly6G was decreased and myelodysplastic features were present in the BM of Dnm2het female mice. A linear distribution of Ly6G+ BM cells along blood vessels was observed in fewer Dnm2het mice than in controls, suggesting that the migration pattern in the marrow is altered. Marrow neutrophils treated with dynamin inhibitor, dynasore, showed increased cell surface CXCR4, suggesting that abnormal migration results in marrow neutrophil retention. Dnm2het female mice also developed splenomegaly secondary to germinal center hyperplasia at younger ages, suggesting perturbed immunity. In summary, female mice with BM Dnm2 haploinsufficiency developed neutropenia as they aged with decreased granulocyte progenitor production and migration defects. Our studies indicate a potential mechanism for the development of chronic idiopathic neutropenia, a disease that predominantly presents in middle-aged women.
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影响因子：
11.8
作者：
Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
通讯作者：
Kirchhausen, Tomas
影响因子：
15.9
作者：
Eash, Kyle J.;Greenbaum, Adam M.;Link, Daniel C.
通讯作者：
Link, Daniel C.
影响因子：
15.9
作者：
Hu, Liping;Huang, Weiqi;Eklund, Elizabeth A.
通讯作者：
Eklund, Elizabeth A.
影响因子：
7.5
作者：
Jahn, Nikolaus;Terzer, Tobias;Bullinger, Lars
通讯作者：
Bullinger, Lars
DOI：
10.1007/978-1-62703-845-4_13
发表时间：
2014-01-01
期刊：
NEUTROPHIL METHODS AND PROTOCOLS, 2ND EDITION
影响因子：
--
作者：
Jennings, Richard T.;Knaus, Ulla G.
通讯作者：
Knaus, Ulla G.