Yong Ryoul Yang1, Hyun-Jun Jang2, Yong Hwa Lee1, Il Shin Kim1, Ho Lee3, Sung Ho Ryu4, Pann-Ghill Suh5. 1. School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea. 2. School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea; Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea. 3. Cancer Experimental Resources Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea. 4. Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea. 5. School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea. Electronic address: pgsuh@unist.ac.kr.
Abstract
INTRODUCTION: Placental vasculogenesis is essential for fetal growth and development, and is affected profoundly by oxygen tension (hypoxia). Hypoxia-inducible factor-1α (HIF-1α), which is stabilized at the protein level in response to hypoxia, is essential for vascular morphogenesis in the placenta. Many studies suggested that responses to hypoxia is influenced by O-GlcNAcylation. O-GlcNAcylation is regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) that catalyze the addition and removal of O-GlcNAc respectively. METHODS: We generated OGA deficient mice and evaluated OGA(-/-) placentas. The analysis of OGA(-/-) placentas was focused on morphological change and placental vasculogenesis. HIF-1α protein stability or transcriptional activity under dysregulation of O-GlcNAcylation were evaluated by Western blot, RT-qPCR and luciferase reporter gene assays in MEFs or MS1 cell line. RESULTS: Deletion of OGA results in defective placental vasculogenesis. OGA(-/-) placentas showed an abnormal placental shape and reduced vasculature in the labyrinth, which caused a developmental delay in the embryos. OGA deletion, which elevates O-GlcNAcylation and downregulates O-GlcNAc transferase (OGT), suppressed HIF-1α stabilization and the transcription of its target genes. In contrast, the overexpression of O-GlcNAc cycling enzymes enhanced the expression and transcriptional activity of HIF-1α. DISCUSSION: These results suggest that OGA plays a critical role in placental vasculogenesis by modulating HIF-1α stabilization. Control of O-GlcNAcylation is essential for placental development.
INTRODUCTION: Placental vasculogenesis is essential for fetal growth and development, and is affected profoundly by oxygen tension (hypoxia). Hypoxia-inducible factor-1α (HIF-1α), which is stabilized at the protein level in response to hypoxia, is essential for vascular morphogenesis in the placenta. Many studies suggested that responses to hypoxia is influenced by O-GlcNAcylation. O-GlcNAcylation is regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) that catalyze the addition and removal of O-GlcNAc respectively. METHODS: We generated OGA deficient mice and evaluated OGA(-/-) placentas. The analysis of OGA(-/-) placentas was focused on morphological change and placental vasculogenesis. HIF-1α protein stability or transcriptional activity under dysregulation of O-GlcNAcylation were evaluated by Western blot, RT-qPCR and luciferase reporter gene assays in MEFs or MS1 cell line. RESULTS: Deletion of OGA results in defective placental vasculogenesis. OGA(-/-) placentas showed an abnormal placental shape and reduced vasculature in the labyrinth, which caused a developmental delay in the embryos. OGA deletion, which elevates O-GlcNAcylation and downregulates O-GlcNAc transferase (OGT), suppressed HIF-1α stabilization and the transcription of its target genes. In contrast, the overexpression of O-GlcNAc cycling enzymes enhanced the expression and transcriptional activity of HIF-1α. DISCUSSION: These results suggest that OGA plays a critical role in placental vasculogenesis by modulating HIF-1α stabilization. Control of O-GlcNAcylation is essential for placental development.
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