title: HOXC9 regulates formation of parachordal lymphangioplasts and the thoracic duct in zebrafish via stabilin 2.
abstract: HOXC9 belongs to the family of homeobox transcription factors, which are regulators of body patterning and development. HOXC9 acts as a negative regulator on blood endothelial cells but its function on lymphatic vessel development has not been studied. The hyaluronan receptor homologs stabilin 1 and stabilin 2 are expressed in endothelial cells but their role in vascular development is poorly understood. This study was aimed at investigating the function of HOXC9, stabilin 2 and stabilin 1 in lymphatic vessel development in zebrafish and in endothelial cells. Morpholino-based expression silencing of HOXC9 repressed parachordal lymphangioblast assembly and thoracic duct formation in zebrafish. HOXC9 positively regulated stabilin 2 expression in zebrafish and in HUVECs and expression silencing of stabilin 2 phenocopied the HOXC9 morphant vascular phenotype. This effect could be compensated by HOXC9 mRNA injection in stabilin 2 morphant zebrafish embryos. Stabilin 1 also regulated parachordal lymphangioblast and thoracic duct formation in zebrafish but acts independently of HOXC9. On a cellular level stabilin 1 and stabilin 2 regulated endothelial cell migration and in-gel sprouting angiogenesis in endothelial cells. HOXC9 was identified as novel transcriptional regulator of parachordal lymphangioblast assembly and thoracic duct formation in zebrafish that acts via stabilin 2. Stabilin 1, which acts independently of HOXC9, has a similar function in zebrafish and both receptors control important cellular processes in endothelial cells.
authors.affiliation: Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Stoll
authors.forename: Susanne
authors.initials: S
authors.lastname: Bartsch
authors.forename: Jens
authors.initials: J
authors.lastname: Kroll
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042601:Lymphatic Vessels / Q000196:embryology*; D008856:Microscopy, Fluorescence; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013897:Thoracic Duct / Q000196:embryology*; D014162:Transfection; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D017931:DNA Primers; D018398:Homeodomain Proteins; D016201:Receptors, Lymphocyte Homing; C449926:STAB1 protein, human; C449927:STAB2 protein, human; D029961:Zebrafish Proteins; C485184:enhanced green fluorescent protein; C560325:hoxc9a protein, zebrafish; D049452:Green Fluorescent Proteins