Liu Xiaofen, Zhang Wenjuan, Jing Changbin, Gao Lei, Fu Cong, Ren Chunguang, Hao Yimei, Cao Mengye, Ma Ke, Pan Weijun, Li Dantong
Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
Front Cell Dev Biol. 2021 Apr 30;9:670654. doi: 10.3389/fcell.2021.670654. eCollection 2021.
Fate determination and expansion of Hematopoietic Stem and Progenitor Cells (HSPCs) is tightly regulated on both transcriptional and post-transcriptional level. Although transcriptional regulation of HSPCs have achieved a lot of advances, its post-transcriptional regulation remains largely underexplored. The small size and high fecundity of zebrafish makes it extraordinarily suitable to explore novel genes playing key roles in definitive hematopoiesis by large-scale forward genetics screening. Here, we reported a novel zebrafish mutant line with a point mutation in gene obtained by ENU mutagenesis and genetic screening, causing an earlier stop codon next to the fifth WD repeat. Gemin5 is an RNA-binding protein with multifunction in post-transcriptional regulation, such as regulating the biogenesis of snRNPs, alternative splicing, stress response, and translation control. The mutants displayed specific deficiency in definitive hematopoiesis without obvious defects during primitive hematopoiesis. Further analysis showed the impaired definitive hematopoiesis was due to defective proliferation of HSPCs. Overall, our results indicate that Gemin5 performs an essential role in regulating HSPCs proliferation.
造血干细胞和祖细胞（HSPCs）的命运决定和扩增在转录和转录后水平上都受到严格调控。尽管HSPCs的转录调控已经取得了很多进展，但其转录后调控仍在很大程度上未被充分探索。斑马鱼体型小且繁殖力高，这使得它非常适合通过大规模正向遗传学筛选来探索在确定性造血中起关键作用的新基因。在此，我们报告了一个通过ENU诱变和遗传筛选获得的具有基因点突变的新型斑马鱼突变系，该突变导致在第五个WD重复序列旁边出现提前终止密码子。Gemin5是一种在转录后调控中具有多种功能的RNA结合蛋白，例如调节snRNP的生物合成、可变剪接、应激反应和翻译控制。这些突变体在确定性造血中表现出特异性缺陷，而在原始造血过程中没有明显缺陷。进一步分析表明，确定性造血受损是由于HSPCs增殖缺陷所致。总体而言，我们的结果表明Gemin5在调节HSPCs增殖中起着至关重要的作用。
