Direct regulation of p53 by miR-142a-3p mediates the survival of hematopoietic stem and progenitor cells in zebrafish.
Direct regulation of p53 by miR-142a-3p mediates the survival of hematopoietic stem and progenitor cells in zebrafish.
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DOI：
10.1038/celldisc.2015.27
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发表时间：
2015
期刊：
影响因子：
33.5
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Lu X;Wei Y;Liu F
造血干细胞和祖细胞具有自我更新和分化为所有血细胞谱系的能力，从而维持造血系统的终生稳态。虽然密集的研究集中在造血干细胞和祖细胞的特化和扩增的协调遗传网络上，但对胚胎发生过程中造血干细胞和祖细胞存活的调控知之甚少。在这里，我们在斑马鱼中产生了两种类型的miR-142 a-3 p遗传突变体，并显示功能丧失突变体显示造血干细胞和祖细胞严重减少。进一步的分析表明，miR-142 a-3 p突变体中增殖减少和过度凋亡归因于p53信号的增加。从机制上讲，我们证明了miR-142 a-3 p在造血干细胞和祖细胞发育过程中直接靶向p53，并且miR-142 a-3 p突变体中的造血干细胞和祖细胞存活缺陷可以通过p53的缺失来挽救。因此，我们的工作揭示了miR-142 a-3 p-p53通路在控制造血干细胞和祖细胞存活中的重要性，从而推进了我们对p53在脊椎动物造血中作用的理解。
Hematopoietic stem and progenitor cells have the capacity to self-renew and differentiate into all blood cell lineages, and thus sustain life-long homeostasis of the hematopoietic system. Although intensive studies have focused on the orchestrated genetic network of hematopoietic stem and progenitor cell specification and expansion, relatively little is known on the regulation of hematopoietic stem and progenitor cell survival during embryogenesis. Here, we generated two types of miR-142a-3p genetic mutants in zebrafish and showed that the loss-of-function mutants displayed severe reduction of hematopoietic stem and progenitor cells. Further analysis showed that the diminished proliferation and excessive apoptosis in miR-142a-3p mutants were attributed to the increased p53 signaling. Mechanistically, we demonstrated that miR-142a-3p directly targets p53 during hematopoietic stem and progenitor cell development, and the hematopoietic stem and progenitor cell survival defect in miR-142a-3p mutants could be rescued by loss of p53. Therefore, our work reveals the significance of the miR-142a-3p-p53 pathway in controlling hematopoietic stem and progenitor cell survival, and thus advances our understanding of the role of p53 in vertebrate hematopoiesis.