title: Control of retinoid levels by CYP26B1 is important for lymphatic vascular development in the mouse embryo.
abstract: During embryogenesis, lymphatic endothelial progenitor cells first arise from a subset of blood vascular endothelial cells in the dorsolateral aspects of the cardinal veins. The molecular cues responsible for defining the regionalisation of such a discrete pool of progenitors remain uncharacterised. Here we identify a novel function for CYP26B1, an enzyme known to play a role in tissue morphogenesis by fine-tuning retinoic acid (RA) concentration, in regulating lymphangiogenesis. Cyp26b1-null mice, in which RA levels are elevated, exhibited an increased number of lymphatic endothelial progenitor cells in the cardinal veins, together with hyperplastic, blood filled lymph sacs and hyperplastic dermal lymphatic vessels. Conversely, mice over-expressing Cyp26b1 had hypoplastic lymph sacs and lymphatic vessels. Our data suggest that RA clearance by CYP26B1 in the vicinity of lymphatic endothelial progenitor cells is important for determining the position and size of the progenitor pool specified. Our studies identify a genetic pathway that underpins the architecture of the developing lymphatics and define CYP26B1 as a novel modulator of lymphatic vascular patterning.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Josephine
authors.initials: J
authors.lastname: Bowles
authors.affiliation: Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide SA 5000, Australia.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Secker
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Christelle
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide SA 5000, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Kazenwadel
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Vy
authors.initials: V
authors.lastname: Truong
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Frampton
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Cameron
authors.initials: C
authors.lastname: Curtis
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Renae
authors.initials: R
authors.lastname: Skoczylas
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Tara-Lynn
authors.initials: TL
authors.lastname: Davidson
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, 431-3192 Hamamatsu, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.affiliation: University of Southern California, Norris Comprehensive Cancer Center, 1450 Biggy St. NRT6501 M/C9601Los Angeles, CA 90033, USA.
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Hong
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.affiliation: Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide SA 5000, Australia; School of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Harvey
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia. Electronic address: m.francois@imb.uq.edu.au.
authors.forename: Mathias
authors.initials: M
authors.lastname: François
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003433:Crosses, Genetic; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D042583:Lymphangiogenesis; D008208:Lymphatic System / Q000196:embryology*; D042601:Lymphatic Vessels / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010641:Phenotype; D000072516:Retinoic Acid 4-Hydroxylase; D012176:Retinoids / Q000378:metabolism*; D015398:Signal Transduction; D019076:Transgenes; D014212:Tretinoin / Q000378:metabolism
chemical_list: D012176:Retinoids; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607081:Cyp26b1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase
keywords: Cyp26b1; Lymphangiogenesis; Lymphatic endothelial cells; Morphogenesis; Prox1; Retinoic acid