The zebrafish miR-462/miR-731 cluster is induced under hypoxic stress via hypoxia-inducible factor 1α and functions in cellular adaptations

• Published in: The FASEB journal Vol. 29; no. 12; p. 4901
• Main Authors: Huang, Chun-Xiao, Chen, Nan, Wu, Xin-Jie, Huang, Cui-Hong, He, Yan, Tang, Rong, Wang, Wei-Min, Wang, Huan-Ling
• Format: Journal Article
• Language: English
• Published: United States 01.12.2015
• Subjects: Adaptation, Physiological; Animals; Cell Line; Humans; Hypoxia - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; MicroRNAs - genetics; Multigene Family; Up-Regulation - physiology; Zebrafish; hypoxamir; cell survival; low oxygen; embryonic development
• ISSN: 1530-6860
• DOI: 10.1096/fj.14-267104

Hypoxia, a unique and essential environmental stress, evokes highly coordinated cellular responses, and hypoxia-inducible factor (HIF) 1 in the hypoxia signaling pathway, an evolutionarily conserved cellular signaling pathway, acts as a master regulator of the transcriptional response to hypoxic stress. MicroRNAs (miRNAs), a major class of posttranscriptional gene expression regulators, also play pivotal roles in orchestrating hypoxia-mediated cellular adaptations. Here, global miRNA expression profiling and quantitative real-time PCR indicated that the up-regulation of the miR-462/miR-731 cluster in zebrafish larvae is induced by hypoxia. It was further validated that miR-462 and miR-731 are up-regulated in a Hif-1α-mediated manner under hypoxia and specifically target ddx5 and ppm1da, respectively. Overexpression of miR-462 and miR-731 represses cell proliferation through blocking cell cycle progress of DNA replication, and induces apoptosis. In situ detection revealed that the miR-462/miR-731 cluster is highly expressed in a consistent and ubiquitous manner throughout the early developmental stages. Additionally, the transcripts become restricted to the notochord, pharyngeal arch, liver, and gut regions from postfertilization d 3 to 5. These data highlight a previously unidentified role of the miR-462/miR-731 cluster as a crucial signaling mediator for hypoxia-mediated cellular adaptations and provide some insights into the potential function of the cluster during embryonic development.