title: Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2.
abstract: The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Yet, our knowledge of the molecular mechanisms underlying lymphatic vessel development is still limited. Here, we show that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of lymphatic vessel development. Endothelial-specific Cdk5 knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc2 as a key substrate of Cdk5 in the lymphatic vasculature, mechanistically linking Cdk5 to lymphatic development and valve morphogenesis. Collectively, our findings show that Cdk5-Foxc2 interaction represents a critical regulator of lymphatic vessel development and the transcriptional network underlying lymphatic vascular remodeling.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Liebl
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Siwei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, 81377 Martinsried, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.affiliation: Department of Oncology, University Hospital of Lausanne, and Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Yan
authors.initials: Y
authors.lastname: Agalarov
authors.affiliation: Department of Oncology, University Hospital of Lausanne, and Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Cansaran Saygili
authors.initials: CS
authors.lastname: Demir
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Hager
authors.affiliation: Department of Psychiatry and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
authors.affiliation: 1] Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany [2] University of Münster, Faculty of Medicine, 48149 Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.affiliation: 1] Department of Oncology, University Hospital of Lausanne, and Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland [2] Ecole Polytechnique Federale de Lausanne (EPFL), Swiss Institute for Experimental Cancer Research (ISREC), 1015 Lausanne, Switzerland.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Stefan
authors.identifier: 0000000251407287
authors.initials: S
authors.lastname: Zahler
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics*; D042601:Lymphatic Vessels / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D013314:Stress, Mechanical
chemical_list: D051858:Forkhead Transcription Factors; C082078:mesenchyme fork head 1 protein; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse