title: Sox7 controls arterial specification in conjunction with hey2 and efnb2 function.
abstract: SoxF family members have been linked to arterio-venous specification events and human pathological conditions, but in contrast to Sox17 and Sox18, a detailed in vivo analysis of a Sox7 mutant model is still lacking. In this study we generated zebrafish sox7 mutants to understand the role of Sox7 during vascular development. By in vivo imaging of transgenic zebrafish lines we show that sox7 mutants display a short circulatory loop around the heart as a result of aberrant connections between the lateral dorsal aorta (LDA) and either the venous primary head sinus (PHS) or the common cardinal vein (CCV). In situ hybridization and live observations in flt4:mCitrine transgenic embryos revealed increased expression levels of flt4 in arterial endothelial cells at the exact location of the aberrant vascular connections in sox7 mutants. An identical circulatory short loop could also be observed in newly generated mutants for hey2 and efnb2. By genetically modulating levels of sox7, hey2 and efnb2 we demonstrate a genetic interaction of sox7 with hey2 and efnb2. The specific spatially confined effect of loss of Sox7 function can be rescued by overexpressing the Notch intracellular domain (NICD) in arterial cells of sox7 mutants, placing Sox7 upstream of Notch in this aspect of arterial development. Hence, sox7 levels are crucial in arterial specification in conjunction with hey2 and efnb2 function, with mutants in all three genes displaying shunt formation and an arterial block.
authors.affiliation: Hubrecht Institute - Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands Erasmus MC Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Dorien M A
authors.initials: DM
authors.lastname: Hermkens
authors.affiliation: Hubrecht Institute - Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: van Impel
authors.affiliation: Hubrecht Institute - Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Urasaki
authors.affiliation: Hubrecht Institute - Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bussmann
authors.affiliation: Erasmus MC Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Henricus J
authors.initials: HJ
authors.lastname: Duckers
authors.affiliation: Hubrecht Institute - Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, 48149 Münster, Germany Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, Westfälische Wilhelms-Universität Münster (WWU), Mendelstrasse 7, 48149 Münster, Germany schultes@ukmuenster.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte-Merker
mesh_terms: D000792:Angiography; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics*; D001158:Arteries / Q000196:embryology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D017403:In Situ Hybridization; D009024:Morphogenesis / Q000502:physiology*; D060172:Morpholinos / Q000235:genetics; D009154:Mutation / Q000235:genetics; D012039:Regional Blood Flow / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055760:SOXF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D060172:Morpholinos; D055760:SOXF Transcription Factors; D040321:Vascular Endothelial Growth Factor Receptor-3; D029961:Zebrafish Proteins; C526281:Sox7 protein, zebrafish; C405954:hey2 protein, zebrafish
keywords: Arterial-venous specification; Sox7; Vascular development; Zebrafish