title: Chemokine signaling directs trunk lymphatic network formation along the preexisting blood vasculature.
abstract: The lymphatic system is crucial for fluid homeostasis, immune responses, and numerous pathological processes. However, the molecular mechanisms responsible for establishing the anatomical form of the lymphatic vascular network remain largely unknown. Here, we show that chemokine signaling provides critical guidance cues directing early trunk lymphatic network assembly and patterning. The chemokine receptors Cxcr4a and Cxcr4b are expressed in lymphatic endothelium, whereas chemokine ligands Cxcl12a and Cxcl12b are expressed in adjacent tissues along which the developing lymphatics align. Loss- and gain-of-function studies in zebrafish demonstrate that chemokine signaling orchestrates the stepwise assembly of the trunk lymphatic network. In addition to providing evidence for a lymphatic vascular guidance mechanism, these results also suggest a molecular basis for the anatomical coalignment of lymphatic and blood vessels.
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, 6B/309, 6 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Young Ryun
authors.initials: YR
authors.lastname: Cha
authors.forename: Misato
authors.initials: M
authors.lastname: Fujita
authors.forename: Matthew
authors.initials: M
authors.lastname: Butler
authors.forename: Sumio
authors.initials: S
authors.lastname: Isogai
authors.forename: Eva
authors.initials: E
authors.lastname: Kochhan
authors.forename: Arndt F
authors.initials: AF
authors.lastname: Siekmann
authors.forename: Brant M
authors.initials: BM
authors.lastname: Weinstein
mesh_terms: D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D008208:Lymphatic System / Q000502:physiology*; D015347:RNA Probes; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C532357:CXCL12b protein, zebrafish; C532358:CXCR4a protein, zebrafish; C471276:CXCR4b protein, zebrafish; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015347:RNA Probes; D019718:Receptors, CXCR4; D029961:Zebrafish Proteins