Spliceosomal component Sf3b1 is essential for hematopoietic differentiation in zebrafish.
Spliceosomal component Sf3b1 is essential for hematopoietic differentiation in zebrafish.
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DOI：
10.1016/j.exphem.2016.05.012
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发表时间：
2016-09
影响因子：
2.6
通讯作者：
Bowman TV
中科院分区：
文献类型：
--
作者：
De La Garza A;Cameron RC;Nik S;Payne SG;Bowman TV
SF3B1（剪接因子3b，亚基1）是骨髓增生异常综合征（MDS）中最常见的突变因子之一。虽然SF3B1突变与MDS病因之间的遗传相关性很强，但目前还没有体内模型来探索SF3B1缺失如何改变血细胞发育。利用斑马鱼突变体，我们发现Sf3b1的正常功能是所有造血谱系所必需的。与MDS患者相似，斑马鱼sf3b1突变体由于在晚期祖细胞阶段成熟受阻而产生大细胞性贫血样表型。突变胚胎也会发生中性粒细胞减少症，因为它们的原始髓细胞不能成熟，并开启分化标记，如l-活蛋白和髓过氧化物酶。相反，背主动脉内的造血内皮细胞产生的最终造血干细胞和祖细胞（HSPCs）大大减少，而动脉内皮细胞则被正确地宿命。Notch信号是内皮细胞向造血细胞转变的必要条件，也是正常的，这表明在sf3b1突变体下游或独立于Notch信号的HSPC诱导被阻断。数据表明，Sf3b1功能在多种血细胞类型的关键分化命运决定中是必要的。斑马鱼sf3b1突变体为探索剪接在造血发育中的作用提供了一种新的动物模型，并为深入研究sf3b1功能障碍为何以及如何阻碍造血分化提供了一个很好的体内系统，可以为MDS的诊断和治疗提供启发。
SF3B1 (Splicing factor 3b, subunit 1) is one of the most commonly mutated factors in myelodysplastic syndrome (MDS). Although the genetic correlation between SF3B1 mutations and MDS etiology are quite strong, no in vivo model currently exists to explore how SF3B1 loss alters blood cell development. Using zebrafish mutants, we show that proper function of Sf3b1 is required for all hematopoietic lineages. Similar to MDS patients, zebrafish sf3b1 mutants develop a macrocytic anemia-like phenotype due to a block in maturation at a late progenitor stage. The mutant embryos also develop neutropenia as their primitive myeloid cells fail to mature and turn on differentiation markers such as l-plastin and myeloperoxidase. In contrast, production of definitive hematopoietic stem and progenitor cells (HSPCs) from hemogenic endothelial cells within the dorsal aorta is greatly diminished, while arterial endothelial cells are correctly fated. Notch signaling, imperative for the endothelial-to-hematopoietic transition, is also normal, indicating HSPC induction is blocked in sf3b1 mutants downstream or independent of Notch signaling. The data demonstrate Sf3b1 function is necessary during key differentiation fate decisions in multiple blood cell types. Zebrafish sf3b1 mutants offer a novel animal model to explore the role of splicing in hematopoietic development and provide an excellent in vivo system to delve into the why and how Sf3b1 dysfunction is detrimental to hematopoietic differentiation, which could enlighten MDS diagnosis and treatment.