Shi Lin-Lin, Ye Ke, Wang Su-Zhen, Hou Chao-Jie, Song An-Kang, Liu Hong, Wang Huan-Ling
Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, 430070 Wuhan, PR China.
Key Lab of Freshwater Animal Breeding, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, 430070 Wuhan, PR China.
Life Sci. 2024 Nov 15;357:123048. doi: 10.1016/j.lfs.2024.123048. Epub 2024 Sep 11.
FoxO1 (Forkhead box O1) belongs to the evolutionarily conserved FoxO subfamily and is involved in diverse physiologic processes, including apoptosis, cell cycle, DNA damage repair, oxidative stress and cell differentiation. FoxO1 plays an important role in regulating the hypoxia microenvironment such as cancers, but its role in hypoxia adaptation remains unclear in animals. To understand the function of foxO1 in hypoxia response, we constructed foxO1a and foxO1b mutant zebrafish using CRISPR/Cas9 technology. It was found that foxO1a and foxO1b destruction affected the hematopoietic system in the early zebrafish embryos. Specifically, FoxO1a and FoxO1b were found to affect the transcriptional activity of runx1, a marker gene for hematopoietic stem cells (HSCs). Moreover, foxO1a and foxO1b had complementary features in hypoxia response, and foxO1a or/and foxO1b destruction resulted in tolerance of zebrafish becoming weakened in hypoxia due to insufficient hemoglobin supply. Additionally, the transcriptional activity of these two genes was demonstrated to be regulated by Hif1α. In conclusion, foxO1a and foxO1b respond to Hif1α-mediated hypoxia response by participating in zebrafish erythropoiesis. These results will provide a theoretical basis for further exploring the function of FoxO1 in hematopoiesis and hypoxia response.
叉头框蛋白O1（FoxO1）属于进化上保守的FoxO亚家族，参与多种生理过程，包括细胞凋亡、细胞周期、DNA损伤修复、氧化应激和细胞分化。FoxO1在调节癌症等缺氧微环境中起重要作用，但其在动物缺氧适应中的作用尚不清楚。为了解FoxO1在缺氧反应中的功能，我们使用CRISPR/Cas9技术构建了foxO1a和foxO1b突变斑马鱼。研究发现，foxO1a和foxO1b的破坏影响斑马鱼早期胚胎的造血系统。具体而言，发现FoxO1a和FoxO1b会影响造血干细胞（HSCs）标记基因runx1的转录活性。此外，foxO1a和foxO1b在缺氧反应中具有互补特征，foxO1a或/和foxO1b的破坏导致斑马鱼由于血红蛋白供应不足而在缺氧时耐受性减弱。此外，这两个基因的转录活性被证明受Hif1α调控。总之，foxO1a和foxO1b通过参与斑马鱼红细胞生成来响应Hif1α介导的缺氧反应。这些结果将为进一步探索FoxO1在造血和缺氧反应中的功能提供理论基础。
