title: The pro-inflammatory signalling regulator Stat4 promotes vasculogenesis of great vessels derived from endothelial precursors.
abstract: Vasculogenic defects of great vessels (GVs) are a major cause of congenital cardiovascular diseases. However, genetic regulators of endothelial precursors in GV vasculogenesis remain largely unknown. Here we show that Stat4, a transcription factor known for its regulatory role of pro-inflammatory signalling, promotes GV vasculogenesis in zebrafish. We find stat4 transcripts highly enriched in nkx2.5+endothelial precursors in the pharynx and demonstrate that genetic ablation of stat4 causes stenosis of pharyngeal arch arteries (PAAs) by suppressing PAAs 3-6 angioblast development. We further show that stat4 is a downstream target of nkx2.5 and that it autonomously promotes proliferation of endothelial precursors of the mesoderm. Mechanistically, stat4 regulates the emerging PAA angioblasts by inhibiting the expression of hdac3 and counteracting the effect of stat1a. Altogether, our study establishes a role for Stat4 in zebrafish great vessel development, and suggests that Stat4 may serve as a therapeutic target for GV defects.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Zhao-Zheng
authors.initials: ZZ
authors.lastname: Meng
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Yin
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Li-Feng
authors.initials: LF
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Gu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001158:Arteries / Q000002:abnormalities / Q000254:growth & development*; D001934:Branchial Region / Q000098:blood supply / Q000254:growth & development; D002318:Cardiovascular Diseases / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004625:Embryo, Nonmammalian; D042783:Endothelial Cells / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000254:growth & development; D023421:Models, Animal; D009024:Morphogenesis / Q000235:genetics*; D060172:Morpholinos / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D060172:Morpholinos; C528182:Nkx2.5 protein, zebrafish; D050797:STAT4 Transcription Factor; C000629154:Stat4 protein, zebrafish; D029961:Zebrafish Proteins; C000625964:HDAC3 protein, zebrafish; D006655:Histone Deacetylases