Rnf111 has a pivotal role in regulating development of definitive hematopoietic stem and progenitor cells through the Smad2/3-Gcsfr/NO axis in zebrafish.

IF 8.2 1区 医学 Q1 HEMATOLOGY Haematologica Pub Date : 2024-10-03 DOI:10.3324/haematol.2024.285438
Xiaohui Liu, Jinghan Sha, Luxiang Wang, Zixuan Wang, Zhou Fang, Xiao Han, Shuiyi Tan, Yi Chen, Hao Yuan, Hugues De The, Jun Zhou, Jun Zhu
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Abstract

The ubiquitination or SUMOylation of hematopoietic related factors plays pivotal roles in hematopoiesis. RNF111, known as a ubiquitin ligase (Ubl), is a newly discovered SUMO-targeted ubiquitin ligase (STUbl) involved in multiple signaling pathways mediated by TGF-β family members. However, its role in hematopoiesis remains unclear. Herein, a heritable Rnf111 mutant zebrafish line was generated by CRISPR/Cas9-mediated genome editing. Impaired hematopoietic stem and progenitor cells (HSPC) of definitive hematopoiesis was found in Rnf111 deficient mutants. Ablation of Rnf111 resulted in decreased phosphorylation of Smad2/3 in HSPC. Definitive endoderm 2 inducer (IDE2), which specifically activates TGF-β signaling and downstream Smad2 phosphorylation, can restore the definitive hematopoiesis in Rnf111-deficient embryos. Further molecular mechanism studies revealed that Gcsfr/NO signaling was an important target pathway of Smad2/3 involved in Rnf111-mediated HSPC development. In conclusion, our study demonstrated that Rnf111 contributes to the development of HSPC by maintaining Smad2/3 phosphorylation and the Gcsfr/NO signaling pathway activation. Keywords: Rnf111, Ubiquitin ligase (UbL), HSPC, Smad2/3, Gcsfr/NO.

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在斑马鱼中,Rnf111通过Smad2/3-Gcsfr/NO轴调控确定性造血干细胞和祖细胞的发育。
造血相关因子的泛素化或 SUMOylation 在造血过程中发挥着关键作用。RNF111被称为泛素连接酶(Ubl),是一种新发现的SUMO靶向泛素连接酶(STUbl),参与了由TGF-β家族成员介导的多种信号通路。然而,它在造血过程中的作用仍不清楚。在此,通过 CRISPR/Cas9 介导的基因组编辑产生了遗传性 Rnf111 突变斑马鱼品系。在 Rnf111 基因缺陷突变体中发现,确定性造血的造血干细胞和祖细胞(HSPC)功能受损。Rnf111的消减导致HSPC中Smad2/3的磷酸化减少。终末内胚层2诱导剂(IDE2)可特异性激活TGF-β信号传导和下游Smad2磷酸化,从而恢复Rnf111缺陷胚胎的终末造血功能。进一步的分子机制研究发现,Gcsfr/NO信号是Smad2/3参与Rnf111介导的HSPC发育的重要靶途径。总之,我们的研究表明,Rnf111通过维持Smad2/3磷酸化和Gcsfr/NO信号通路的激活来促进HSPC的发育。关键词Rnf111 泛素连接酶(UbL) HSPC Smad2/3 Gcsfr/NO
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来源期刊
Haematologica
Haematologica 医学-血液学
CiteScore
14.10
自引率
2.00%
发文量
349
审稿时长
3-6 weeks
期刊介绍: Haematologica is a journal that publishes articles within the broad field of hematology. It reports on novel findings in basic, clinical, and translational research. Scope: The scope of the journal includes reporting novel research results that: Have a significant impact on understanding normal hematology or the development of hematological diseases. Are likely to bring important changes to the diagnosis or treatment of hematological diseases.
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