Deletion of the <i>foxO4</i> Gene Increases Hypoxia Tolerance in Zebrafish
Oxygen homeostasis is an important organizing principle for understanding development, physiology, disease, and evolution. Under various physiological and pathological states, organisms experience oxygen deficiency or hypoxia. FoxO4 has been recognized as an important transcriptional regulator invol...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/10/8942 |
| _version_ | 1797599738725400576 |
|---|---|
| author | Linlin Shi Axin Zhang Hong Liu Huanling Wang |
| author_facet | Linlin Shi Axin Zhang Hong Liu Huanling Wang |
| author_sort | Linlin Shi |
| collection | DOAJ |
| description | Oxygen homeostasis is an important organizing principle for understanding development, physiology, disease, and evolution. Under various physiological and pathological states, organisms experience oxygen deficiency or hypoxia. FoxO4 has been recognized as an important transcriptional regulator involved in a variety of cellular functions, including proliferation, apoptosis, differentiation, and stress resistance, but its role in hypoxia adaptation mechanisms in animals is not so clear. To explore the role of <i>foxO4</i> in the hypoxia response, we detected the expression of <i>foxO4</i> and the regulatory relationship between Hif1α and <i>foxO4</i> under hypoxic conditions. It was found that the expression of <i>foxO4</i> was up-regulated in ZF4 cells and zebrafish tissues after hypoxia treatment, and Hif1α could directly target the HRE of the <i>foxO4</i> promoter to regulate <i>foxO4</i> transcription, indicating that <i>foxO4</i> was involved in the hypoxia response by the Hif1α-mediated pathway. Furthermore, we obtained <i>foxO4</i> knockout zebrafish and found that the disruption of <i>foxO4</i> increased the tolerance to hypoxia. Further research found that the oxygen consumption and locomotor activity of <i>foxO4</i><sup>−/−</sup> zebrafish were lower than those of WT zebrafish, as was true for NADH content, NADH/NAD<sup>+</sup> rate, and expression of mitochondrial respiratory chain complex-related genes. This suggests that disruption of <i>foxO4</i> reduced the oxygen demand threshold of the organism, which explained why the <i>foxO4<sup>−/−</sup></i> zebrafish were more tolerant to hypoxia than WT zebrafish. These results will provide a theoretical basis for further study of the role of <i>foxO4</i> in the hypoxia response. |
| first_indexed | 2024-03-11T03:39:32Z |
| format | Article |
| id | doaj.art-6afeab147fae4bc08ad84e789560457d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:39:32Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6afeab147fae4bc08ad84e789560457d2023-11-18T01:44:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012410894210.3390/ijms24108942Deletion of the <i>foxO4</i> Gene Increases Hypoxia Tolerance in ZebrafishLinlin Shi0Axin Zhang1Hong Liu2Huanling Wang3Key Lab of Freshwater Animal Breeding/Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan 430070, ChinaKey Lab of Freshwater Animal Breeding/Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan 430070, ChinaKey Lab of Freshwater Animal Breeding/Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan 430070, ChinaKey Lab of Freshwater Animal Breeding/Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Fishery, Huazhong Agricultural University, Wuhan 430070, ChinaOxygen homeostasis is an important organizing principle for understanding development, physiology, disease, and evolution. Under various physiological and pathological states, organisms experience oxygen deficiency or hypoxia. FoxO4 has been recognized as an important transcriptional regulator involved in a variety of cellular functions, including proliferation, apoptosis, differentiation, and stress resistance, but its role in hypoxia adaptation mechanisms in animals is not so clear. To explore the role of <i>foxO4</i> in the hypoxia response, we detected the expression of <i>foxO4</i> and the regulatory relationship between Hif1α and <i>foxO4</i> under hypoxic conditions. It was found that the expression of <i>foxO4</i> was up-regulated in ZF4 cells and zebrafish tissues after hypoxia treatment, and Hif1α could directly target the HRE of the <i>foxO4</i> promoter to regulate <i>foxO4</i> transcription, indicating that <i>foxO4</i> was involved in the hypoxia response by the Hif1α-mediated pathway. Furthermore, we obtained <i>foxO4</i> knockout zebrafish and found that the disruption of <i>foxO4</i> increased the tolerance to hypoxia. Further research found that the oxygen consumption and locomotor activity of <i>foxO4</i><sup>−/−</sup> zebrafish were lower than those of WT zebrafish, as was true for NADH content, NADH/NAD<sup>+</sup> rate, and expression of mitochondrial respiratory chain complex-related genes. This suggests that disruption of <i>foxO4</i> reduced the oxygen demand threshold of the organism, which explained why the <i>foxO4<sup>−/−</sup></i> zebrafish were more tolerant to hypoxia than WT zebrafish. These results will provide a theoretical basis for further study of the role of <i>foxO4</i> in the hypoxia response.https://www.mdpi.com/1422-0067/24/10/8942<i>foxO4</i>hypoxiazebrafishoxygen consumption |
| spellingShingle | Linlin Shi Axin Zhang Hong Liu Huanling Wang Deletion of the <i>foxO4</i> Gene Increases Hypoxia Tolerance in Zebrafish International Journal of Molecular Sciences <i>foxO4</i> hypoxia zebrafish oxygen consumption |
| title | Deletion of the <i>foxO4</i> Gene Increases Hypoxia Tolerance in Zebrafish |
| title_full | Deletion of the <i>foxO4</i> Gene Increases Hypoxia Tolerance in Zebrafish |
| title_fullStr | Deletion of the <i>foxO4</i> Gene Increases Hypoxia Tolerance in Zebrafish |
| title_full_unstemmed | Deletion of the <i>foxO4</i> Gene Increases Hypoxia Tolerance in Zebrafish |
| title_short | Deletion of the <i>foxO4</i> Gene Increases Hypoxia Tolerance in Zebrafish |
| title_sort | deletion of the i foxo4 i gene increases hypoxia tolerance in zebrafish |
| topic | <i>foxO4</i> hypoxia zebrafish oxygen consumption |
| url | https://www.mdpi.com/1422-0067/24/10/8942 |
| work_keys_str_mv | AT linlinshi deletionoftheifoxo4igeneincreaseshypoxiatoleranceinzebrafish AT axinzhang deletionoftheifoxo4igeneincreaseshypoxiatoleranceinzebrafish AT hongliu deletionoftheifoxo4igeneincreaseshypoxiatoleranceinzebrafish AT huanlingwang deletionoftheifoxo4igeneincreaseshypoxiatoleranceinzebrafish |