Pkd1 Regulates Lymphatic Vascular Morphogenesis during Development

• Published in: Cell reports (Cambridge) Vol. 7; no. 3; pp. 623 - 633
• Main Authors: Coxam, Baptiste, Sabine, Amélie, Bower, Neil I., Smith, Kelly A., Pichol-Thievend, Cathy, Skoczylas, Renae, Astin, Jonathan W., Frampton, Emmanuelle, Jaquet, Muriel, Crosier, Philip S., Parton, Robert G., Harvey, Natasha L., Petrova, Tatiana V., Schulte-Merker, Stefan, Francois, Mathias, Hogan, Benjamin M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2014; Elsevier
• Subjects: Animals; Animals, Genetically Modified; Cells, Cultured; Danio rerio; Embryo, Mammalian - metabolism; Embryonic Development; Endothelial Cells - cytology; Endothelial Cells - metabolism; Humans; Intercellular Junctions - metabolism; Lymph Nodes - growth & development; Lymph Nodes - metabolism; Lymphangiogenesis; Lymphatic Vessels - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Phenotype; Polycystic Kidney, Autosomal Dominant - genetics; Polycystic Kidney, Autosomal Dominant - metabolism; Polycystic Kidney, Autosomal Dominant - pathology; TRPP Cation Channels - antagonists & inhibitors; TRPP Cation Channels - genetics; TRPP Cation Channels - metabolism; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.03.063

Lymphatic vessels arise during development through sprouting of precursor cells from veins, which is regulated by known signaling and transcriptional mechanisms. The ongoing elaboration of vessels to form a network is less well understood. This involves cell polarization, coordinated migration, adhesion, mixing, regression, and shape rearrangements. We identified a zebrafish mutant, lymphatic and cardiac defects 1 (lyc1), with reduced lymphatic vessel development. A mutation in polycystic kidney disease 1a was responsible for the phenotype. PKD1 is the most frequently mutated gene in autosomal dominant polycystic kidney disease (ADPKD). Initial lymphatic precursor sprouting is normal in lyc1 mutants, but ongoing migration fails. Loss of Pkd1 in mice has no effect on precursor sprouting but leads to failed morphogenesis of the subcutaneous lymphatic network. Individual lymphatic endothelial cells display defective polarity, elongation, and adherens junctions. This work identifies a highly selective and unexpected role for Pkd1 in lymphatic vessel morphogenesis during development. [Display omitted] •Identification of an unexpected role for the ADPKD gene Pkd1 in lymphatic development•Pkd1 regulates endothelial cell sprouting and cell-cell junctions in vitro•Pkd1 regulates cell polarity and cell-cell junctions in developing vessels in mice The earliest steps in lymphatic vascular development are increasingly well defined, but the processes and molecules that control ongoing network morphogenesis remain to be understood. In this study, Coxam et al. show that the autosomal dominant polycystic kidney disease (ADPKD) gene Pkd1 regulates lymphatic endothelial cell polarity, shape, and adhesion during migration, vessel morphogenesis, and lymphatic vascular network elaboration.