title: Semaphorin 3G Provides a Repulsive Guidance Cue to Lymphatic Endothelial Cells via Neuropilin-2/PlexinD1.
abstract: The vertebrate circulatory system is composed of closely related blood and lymphatic vessels. It has been shown that lymphatic vascular patterning is regulated by blood vessels during development, but its molecular mechanisms have not been fully elucidated. Here, we show that the artery-derived ligand semaphorin 3G (Sema3G) and the endothelial cell receptor PlexinD1 play a role in lymphatic vascular patterning. In mouse embryonic back skin, genetic inactivation of Sema3G or PlexinD1 results in abnormal artery-lymph alignment and reduced lymphatic vascular branching. Conditional ablation in mice demonstrates that PlexinD1 is primarily required in lymphatic endothelial cells (LECs). In vitro analyses show that Sema3G binds to neuropilin-2 (Nrp2), which forms a receptor complex with PlexinD1. Sema3G induces cell collapse in an Nrp2/PlexinD1-dependent manner. Our findings shed light on a molecular mechanism by which LECs are distributed away from arteries and form a branching network during lymphatic vascular development.
authors.affiliation: Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Uemura
authors.affiliation: Department of Ophthalmology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan. Electronic address: mhirashi@med.kobe-u.ac.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirashima
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000196:embryology; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000098:blood supply / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D042601:Lymphatic Vessels / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D039943:Neuropilin-2 / Q000378:metabolism*; D011485:Protein Binding; D039961:Semaphorins / Q000378:metabolism*; D012867:Skin / Q000196:embryology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D039943:Neuropilin-2; C473552:Plxnd1 protein, mouse; D039961:Semaphorins; C505763:semaphorin 3G, mouse
keywords: development; endothelial cells; lymphatic vessels; mouse