BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

A novel role of Hippo-Yap/TAZ signaling pathway in lymphatic vascular development

  • Cha, Boksik (Daegu Gyeongbuk Medical Innovation Foundation) ;
  • Moon, Sungjin (Department of Biological Science, Kangwon National University) ;
  • Kim, Wantae (Department of Biochemistry, Chungnam National University)
  • Received : 2021.01.25
  • Accepted : 2021.03.03
  • Published : 2021.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

The lymphatic vasculature plays important role in regulating fluid homeostasis, intestinal lipid absorption, and immune surveillance in humans. Malfunction of lymphatic vasculature leads to several human diseases. Understanding the fundamental mechanism in lymphatic vascular development not only expand our knowledge, but also provide a new therapeutic insight. Recently, Hippo-YAP/TAZ signaling pathway, a key mechanism of organ size and tissue homeostasis, has emerged as a critical player that regulate lymphatic specification, sprouting, and maturation. In this review, we discuss the mechanistic regulation and pathophysiological significant of Hippo pathway in lymphatic vascular development.

Keywords

Acknowledgement

We sincerely apologize as we are unable to cite multiple key research papers due to space limitations. We thank Dr. R. Sathish Srinivasan for his insightful comments. This work is supported by the grant from the National Research Foundation of Korea (2020R1F1A1060680) to B. Cha (2020R1C1C100705011), S. Moon, and (2021R1A2C4001704) W. Kim.

References

  1. Adams RH and Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8, 464-478 https://doi.org/10.1038/nrm2183
  2. Oliver G and Detmar M (2002) The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev 16, 773-783 https://doi.org/10.1101/gad.975002
  3. Harvey NL, Srinivasan RS, Dillard ME et al (2005) Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat Genet 37, 1072-1081 https://doi.org/10.1038/ng1642
  4. Dieterich LC, Seidel CD and Detmar M (2014) Lymphatic vessels: new targets for the treatment of inflammatory diseases. Angiogenesis 17, 359-371 https://doi.org/10.1007/s10456-013-9406-1
  5. Lim K-C, Hosoya T, Brandt W et al (2012) Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning. J Clin Invest 122, 3705-3717 https://doi.org/10.1172/JCI61619
  6. Martel C, Li W, Fulp B et al (2013) Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J Clin Invest 123, 1571-1579 https://doi.org/10.1172/JCI63685
  7. Randolph GJ, Angeli V and Swartz MA (2005) Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 5, 617-628 https://doi.org/10.1038/nri1670
  8. Da Mesquita S, Louveau A, Vaccari A et al (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature 560, 185-191 https://doi.org/10.1038/s41586-018-0368-8
  9. Wiig H, Schroder A, Neuhofer W et al (2013) Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. J Clin Invest 123, 2803-2815 https://doi.org/10.1172/JCI60113
  10. Ho YC and Srinivasan RS (2020) Lymphatic vasculature in energy homeostasis and obesity. Front Physiol 11, 3 https://doi.org/10.3389/fphys.2020.00003
  11. Vaahtomeri K, Karaman S, Makinen T and Alitalo K (2017) Lymphangiogenesis guidance by paracrine and pericellular factors. Genes Dev 31, 1615-1634 https://doi.org/10.1101/gad.303776.117
  12. Cha B, Geng X, Mahamud MR et al (2016) Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves. Genes Dev 30, 1454-1469 https://doi.org/10.1101/gad.282400.116
  13. Tatin F, Taddei A, Weston A et al (2013) Planar cell polarity protein Celsr1 regulates endothelial adherens junctions and directed cell rearrangements during valve morphogenesis. Dev Cell 26, 31-44 https://doi.org/10.1016/j.devcel.2013.05.015
  14. Sabine A, Agalarov Y, Hajjami HM-E et al (2012) Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphaticvalve formation. Dev Cell 22, 430-445 https://doi.org/10.1016/j.devcel.2011.12.020
  15. McLatchie LM, Fraser NJ, Main MJ et al (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333-339 https://doi.org/10.1038/30666
  16. Murtomaki A, Uh MK, Choi YK et al (2013) Notch1 functions as a negative regulator of lymphatic endothelial cell differentiation in the venous endothelium. Development 140, 2365-2376 https://doi.org/10.1242/dev.083865
  17. Dunworth WP, Cardona-Costa J, Bozkulak EC et al (2014) Bone morphogenetic protein 2 signaling negatively modulates lymphatic development in vertebrate embryos. Circ Res 114, 56-66 https://doi.org/10.1161/CIRCRESAHA.114.302452
  18. Bazigou E, Xie S, Chen C et al (2009) Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell 17, 175-186 https://doi.org/10.1016/j.devcel.2009.06.017
  19. Kim W and Jho EH (2018) The history and regulatory mechanism of the Hippo pathway. BMB Rep 51, 106-118 https://doi.org/10.5483/BMBRep.2018.51.3.022
  20. Misra JR and Irvine KD (2018) The Hippo signaling network and its biological functions. Annu Rev Genet 52, 65-87 https://doi.org/10.1146/annurev-genet-120417-031621
  21. Ma S, Meng Z, Chen R and Guan K-L (2019) The Hippo pathway: biology and pathophysiology. Annu Rev Biochem 88, 577-604 https://doi.org/10.1146/annurev-biochem-013118-111829
  22. Zanconato F, Cordenonsi M and Piccolo S (2016) YAP/TAZ at the roots of cancer. Cancer Cell 29, 783-803 https://doi.org/10.1016/j.ccell.2016.05.005
  23. Totaro A, Panciera T and Piccolo S (2018) YAP/TAZ upstream signals and downstream responses. Nat Cell Biol 20, 888-899 https://doi.org/10.1038/s41556-018-0142-z
  24. Piccolo S, Dupont S and Cordenonsi M (2014) The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev 94, 1287-1312 https://doi.org/10.1152/physrev.00005.2014
  25. Meng Z, Moroishi T and Guan KL (2016) Mechanisms of Hippo pathway regulation. Genes Dev 30, 1-17 https://doi.org/10.1101/gad.274027.115
  26. Yu FX, Zhao B and Guan KL (2015) Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811-828 https://doi.org/10.1016/j.cell.2015.10.044
  27. Justice RW, Woods ODF, Nol M and Bryant PJ (1995) The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev 9, 534-546 https://doi.org/10.1101/gad.9.5.534
  28. Xu T, Wang W, Zhang S, Stewart RA and Yu W (1995) Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053-1063 https://doi.org/10.1242/dev.121.4.1053
  29. Tapon N, Harvey KF, Bell DW et al (2002) Salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467-478 https://doi.org/10.1016/S0092-8674(02)00824-3
  30. Harvey KF, Pfleger CM and Hariharan IK (2003) The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457-467 https://doi.org/10.1016/S0092-8674(03)00557-9
  31. Udan RS, Kango-Singh M, Nolo R, Tao C and Halder G (2003) Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol 5, 914-920 https://doi.org/10.1038/ncb1050
  32. Wu S, Huang J, Dong J and Pan D (2003) Hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114, 445-456 https://doi.org/10.1016/S0092-8674(03)00549-X
  33. Zheng Y and Pan D (2019) The Hippo signaling pathway in development and disease. Dev Cell 50, 264-282 https://doi.org/10.1016/j.devcel.2019.06.003
  34. Yu FX and Guan KL (2013) The Hippo pathway: regulators and regulations. Genes Dev 27, 355-371 https://doi.org/10.1101/gad.210773.112
  35. Zhao B, Li L, Tumaneng K, Wang CY and Guan KL (2010) A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev 24, 72-85 https://doi.org/10.1101/gad.1843810
  36. Zhao B, Wei X, Li W et al (2007) Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21, 2747-2761 https://doi.org/10.1101/gad.1602907
  37. Huang W, Lv X, Liu C et al (2012) The N-terminal phosphodegron targets TAZ/WWTR1 protein for SCFbetaTrCP-dependent degradation in response to phosphatidylinositol 3-kinase inhibition. J Biol Chem 287, 26245-26253 https://doi.org/10.1074/jbc.M112.382036
  38. Zhang L, Ren F, Zhang Q, Chen Y, Wang B and Jiang J (2008) The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev Cell 14, 377-387 https://doi.org/10.1016/j.devcel.2008.01.006
  39. Wu S, Liu Y, Zheng Y, Dong J and Pan D (2008) The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell 14, 388-398 https://doi.org/10.1016/j.devcel.2008.01.007
  40. Kim J, Kim YH, Kim J et al (2017) YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J Clin Invest 127, 3441-3461 https://doi.org/10.1172/JCI93825
  41. Sakabe M, Fan J, Odaka Y et al (2017) YAP/TAZ-CDC42 signaling regulates vascular tip cell migration. Proc Natl Acad Sci U S A 114, 10918-10923 https://doi.org/10.1073/pnas.1704030114
  42. Wang X, Valls AF, Schermann G et al (2017) YAP/TAZ orchestrate VEGF signaling during developmental angiogenesis. Dev Cell 42, 462-478.e7 https://doi.org/10.1016/j.devcel.2017.08.002
  43. Giampietro C, Disanza A, Bravi L et al (2015) The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling. J Cell Biol 211, 1177-1192 https://doi.org/10.1083/jcb.201501089
  44. Cha B, Ho YC, Geng X et al (2020) YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling. Development 147, dev195453 https://doi.org/10.1242/dev.195453
  45. Cho H, Kim J, Ahn JH et al (2019) YAP and TAZ negatively regulate Prox1 during developmental and pathologic lymphangiogenesis. Circ Res 124, 225-242 https://doi.org/10.1161/CIRCRESAHA.118.313707
  46. Sabine A, Bovay E, Demir CS et al (2015) FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature. J Clin Invest 125, 3861-3877 https://doi.org/10.1172/JCI80454
  47. Plouffe SW, Lin KC, Moore JL 3rd et al (2018) The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell. J Biol Chem 293, 11230-11240 https://doi.org/10.1074/jbc.RA118.002715
  48. Sun C, Mello VD, Mohamed A et al (2017) Common and distinctive functions of the Hippo effectors Taz and Yap in skeletal muscle stem cell function. Stem Cells 35, 1958-1972 https://doi.org/10.1002/stem.2652
  49. Escobedo N and Oliver G (2016) Lymphangiogenesis: origin, specification, and cell fate determination. Annu Rev Cell Dev Biol 32, 677-691 https://doi.org/10.1146/annurev-cellbio-111315-124944
  50. Bui K and Hong YK (2020) Ras pathways on Prox1 and lymphangiogenesis: insights for therapeutics. Front Cardiovasc Med 7, 597374 https://doi.org/10.3389/fcvm.2020.597374
  51. Grimm L, Nakajima H, Chaudhury S et al (2019) Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk. Elife 8, e42881 https://doi.org/10.7554/eLife.42881
  52. Azad T, Rensburg HJJ, Lightbody ED et al (2018) A LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis. Nat Commun 9, 1061 https://doi.org/10.1038/s41467-018-03278-w
  53. Yeh YW, Cheng CC, Yang ST et al (2017) Targeting the VEGF-C/VEGFR3 axis suppresses Slug-mediated cancer metastasis and stemness via inhibition of KRAS/YAP1 signaling. Oncotarget 8, 5603-5618 https://doi.org/10.18632/oncotarget.13629
  54. Hamaratoglu F, Willecke M, Kango-Singh M et al (2006) The tumour-suppressor genes NF2/Merlin and expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol 8, 27-36 https://doi.org/10.1038/ncb1339
  55. Willecke M, Hamaratoglu F, Kango-Singh M et al (2006) The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size. Curr Biol 16, 2090-2100 https://doi.org/10.1016/j.cub.2006.09.005
  56. Kuta A, Mao Y, Martin T et al (2016) Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae. Development 143, 2367-2375 https://doi.org/10.1242/dev.131037
  57. Alders M, Al-Gazali L, Cordeiro I et al (2014) Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Hum Genet 133, 1161-1167 https://doi.org/10.1007/s00439-014-1456-y
  58. Betterman KL, Sutton DL, Secker GA et al (2020) Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. J Clin Invest 130, 3315-3328 https://doi.org/10.1172/jci99027
  59. Cheong SS, Akram KM, Matellan C et al (2020) The planar polarity component VANGL2 is a key regulator of mechanosignaling. Front Cell Dev Biol 8, 577201 https://doi.org/10.3389/fcell.2020.577201
  60. Choi HJ, Zhang H, Park H et al (2015) Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2. Nat Commun 6, 6943 https://doi.org/10.1038/ncomms7943
  61. Hagerling R, Hoppe E, Dierkes C et al (2018) Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds. EMBO J 37, e98271
  62. Yang Y, Cha B, Motawe ZY, Srinivasan RS, Scallan JP (2019) VE-Cadherin is required for lymphatic valve formation and maintenance. Cell Rep 28, 2397-2412.e4 https://doi.org/10.1016/j.celrep.2019.07.072
  63. Au AC, Hernandez PA, Lieber E et al (2010) Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans. Am J Hum Genet 87, 436-444 https://doi.org/10.1016/j.ajhg.2010.08.008
  64. Liu X, Yang N, Figel SA et al (2013) PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene 32, 1266-1273 https://doi.org/10.1038/onc.2012.147
  65. Wilson KE, Li YW, Yang N, Shen H, Orillion AR and Zhang J (2014) PTPN14 forms a complex with Kibra and LATS1 proteins and negatively regulates the YAP oncogenic function. J Biol Chem 289, 23693-23700 https://doi.org/10.1074/jbc.M113.534701
  66. Wang W, Huang J, Wang X et al (2012) PTPN14 is required for the density-dependent control of YAP1. Genes Dev 26, 1959-1971 https://doi.org/10.1101/gad.192955.112
  67. Dupont S, Morsut L, Aragona M et al (2011) Role of YAP/TAZ in mechanotransduction. Nature 474, 179-183 https://doi.org/10.1038/nature10137
  68. Panciera T, Azzolin L, Cordenonsi M et al (2017) Mechanobiology of YAP and TAZ in physiology and disease. Nat Rev Mol Cell Biol 18, 758-770 https://doi.org/10.1038/nrm.2017.87
  69. Wang KC, Yeh YT, Nguyen P et al (2016) Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis. Proc Natl Acad Sci U S A 113, 11525-11530 https://doi.org/10.1073/pnas.1613121113
  70. Wang L, Luo JY, Li B et al (2016) Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540, 579-582 https://doi.org/10.1038/nature20602
  71. Nakajima H, Yamamoto K, Agarwala S et al (2017) Flow-dependent endothelial YAP regulation contributes to vessel maintenance. Dev Cell 40, 523-536.e6 https://doi.org/10.1016/j.devcel.2017.02.019
  72. Nakajima H and Mochizuki N (2017) Flow pattern-dependent endothelial cell responses through transcriptional regulation. Cell Cycle 16, 1893-1901 https://doi.org/10.1080/15384101.2017.1364324
  73. Choi D, Park E, Jung E et al (2017) Laminar flow downregulates Notch activity to promote lymphatic sprouting. J Clin Invest 127, 1225-1240 https://doi.org/10.1172/JCI87442
  74. Geng X, Yanagida K, Akwii RG et al (2020) S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling. JCI Insight 5, e137652 https://doi.org/10.1172/jci.insight.137652
  75. Liu Z, Wei Y, Zhang L et al (2019) Induction of store-operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ. Oncogene 38, 120-139 https://doi.org/10.1038/s41388-018-0425-7
  76. Choi D, Park E, Jung E et al (2019) Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance. JCI Insight 4, e125068 https://doi.org/10.1172/jci.insight.125068
  77. Nonomura K, Lukacs V, Sweet DT et al (2018) Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation. Proc Natl Acad Sci U S A 115, 12817-12822 https://doi.org/10.1073/pnas.1817070115
  78. Pathak MM, Nourse JL, Tran T et al (2014) Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells. Proc Natl Acad Sci U S A 111, 16148-16153 https://doi.org/10.1073/pnas.1409802111
  79. Zhou T, Gao B, Fan Y et al (2020) Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-β-catenin. Elife 9, e52779 https://doi.org/10.7554/elife.52779
  80. Wang L, You X, Lotinun S, Zhang L, Wu N and Zou W (2020) Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk. Nat Commun 11, 282 https://doi.org/10.1038/s41467-019-14146-6
  81. Sun Z, Guo SS and Fassler R (2016) Integrin-mediated mechanotransduction. J Cell Biol 215, 445-456 https://doi.org/10.1083/jcb.201609037
  82. Rausch V and Hansen CG (2020) The Hippo pathway, YAP/TAZ, and the plasma membrane. Trends Cell Biol 30, 32-48 https://doi.org/10.1016/j.tcb.2019.10.005
  83. Frye M, Taddei A, Dierkes C et al (2018) Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Nat Commun 9, 1511 https://doi.org/10.1038/s41467-018-03959-6
  84. Aragona M, Panciera T, Manfrin A et al (2013) A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047-1059 https://doi.org/10.1016/j.cell.2013.07.042
  85. Planas-Paz L, Strilic B, Goedecke A, Breier G, Fassler R and Lammert E (2012) Mechanoinduction of lymph vessel expansion. EMBO J 31, 788-804 https://doi.org/10.1038/emboj.2011.456
  86. Yu FX, Zhao B, Panupinthu N et al (2012) Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150, 780-791 https://doi.org/10.1016/j.cell.2012.06.037
  87. Hoopes SL, Willcockson HH and and Caron KM (2008) Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice. PLoS One 7, e45261 https://doi.org/10.1371/journal.pone.0045261
  88. Lee SJ, Chan TH, Chen TC, Liao BK, Hwang PP and Lee H (2008) LPA1 is essential for lymphatic vessel development in zebrafish. FASEB J 22, 3706-3715 https://doi.org/10.1096/fj.08-106088
  89. Sumida H, Noguchi K, Kihara Y et al (2010) LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. Blood 116, 5060-5070 https://doi.org/10.1182/blood.v116.21.5060.5060
  90. Lin CI, Chen CN, Huang MT et al (2008) Lysophosphatidic acid up-regulates vascular endothelial growth factor-C and lymphatic marker expressions in human endothelial cells. Cell Mol Life Sci 65, 2740-2751 https://doi.org/10.1007/s00018-008-8314-9
  91. Yoon CM, Hong BS, Moon HG et al (2008) Sphingosine1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways. Blood 112, 1129-1138
  92. Kim W, Kim M and Jho EH (2013) Wnt/beta-catenin signalling: from plasma membrane to nucleus. Biochem J 450, 9-21 https://doi.org/10.1042/BJ20121284
  93. Nusse R and Clevers H (2017) Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985-999 https://doi.org/10.1016/j.cell.2017.05.016
  94. Clevers H and Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149, 1192-1205 https://doi.org/10.1016/j.cell.2012.05.012
  95. Kim M and Jho EH (2014) Cross-talk between Wnt/beta-catenin and Hippo signaling pathways: a brief review. BMB Rep 47, 540-545 https://doi.org/10.5483/BMBRep.2014.47.10.177
  96. Azzolin L, Zanconato F, Bresolin S et al (2012) Role of TAZ as mediator of Wnt signaling. Cell 151, 1443-1456 https://doi.org/10.1016/j.cell.2012.11.027
  97. Azzolin L, Panciera T, Soligo S et al (2014) YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 158, 157-170 https://doi.org/10.1016/j.cell.2014.06.013
  98. Park HW, Kim YC, Yu B et al (2015) Alternative Wnt signaling activates YAP/TAZ. Cell 162, 780-794 https://doi.org/10.1016/j.cell.2015.07.013
  99. Lutze G, Haarmann A, Toukam JAD, Buttler K, Wilting J and Becker J (2019) Non-canonical WNT-signaling controls differentiation of lymphatics and extension lymphangiogenesis via RAC and JNK signaling. Sci Rep 9, 4739 https://doi.org/10.1038/s41598-019-41299-7
  100. Cha B, Geng X, Mahamud MR et al (2018) Complementary Wnt sources regulate lymphatic vascular development via PROX1-dependent Wnt/β-catenin signaling. Cell Rep 25, 571-584.e5 https://doi.org/10.1016/j.celrep.2018.09.049
  101. Majumder S, Crabtree JS, Golde TE, Minter LM, Osborne BA and Miele L (2021) Targeting Notch in oncology: the path forward. Nat Rev Drug Discov 20, 125-144 https://doi.org/10.1038/s41573-020-00091-3
  102. Bray SJ (2016) Notch signalling in context. Nat Rev Mol Cell Biol 17, 722-735 https://doi.org/10.1038/nrm.2016.94
  103. Tschaharganeh DF, Chen X, Latzko P et al (2013) Yesassociated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology 144, 1530-1542.e12 https://doi.org/10.1053/j.gastro.2013.02.009
  104. Kim W, Khan SK, Gvozdenovic-Jeremic J et al (2017) Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest 127, 137-152 https://doi.org/10.1172/JCI88486
  105. Kang J, Yoo J, Lee S et al (2010) An exquisite crosscontrol mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells. Blood 116, 140-150 https://doi.org/10.1182/blood.v116.21.140.140
  106. Fatima A, Culver A, Culver F et al (2014) Murine Notch1 is required for lymphatic vascular morphogenesis during development. Dev Dyn 243, 957-964 https://doi.org/10.1002/dvdy.24129
  107. Niessen K, Zhang G, Ridgway JB et al (2011) The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development. Blood 118, 1989-1997 https://doi.org/10.1182/blood.v118.21.1989.1989
  108. Srinivasan RS, Dillard ME, Lagutin OV et al (2007) Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev 21, 2422-2432 https://doi.org/10.1101/gad.1588407
  109. Wigle JT and Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98, 769-778 https://doi.org/10.1016/S0092-8674(00)81511-1
  110. Yaniv K, Isogai S, Castranova D, Dye L, Hitomi J and Weinstein BM (2006) Live imaging of lymphatic development in the zebrafish. Nat Med 12, 711-716 https://doi.org/10.1038/nm1427
  111. Srinivasan RS, Geng X, Yang Y et al (2010) The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev 24, 696-707 https://doi.org/10.1101/gad.1859310
  112. Hong YK, Harvey N, Noh YH et al (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 225, 351-357 https://doi.org/10.1002/dvdy.10163
  113. Francois M, Caprini A, Hosking B et al (2008) Sox18 induces development of the lymphatic vasculature in mice. Nature 456, 643-647 https://doi.org/10.1038/nature07391
  114. Srinivasan RS, Escobedo N, Yang Y et al (2014) The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors. Genes Dev 28, 2175-2187 https://doi.org/10.1101/gad.216226.113
  115. Koltowska K, Lagendijk AK, Pichol-Thievend C et al (2015) Vegfc regulates bipotential precursor division and Prox1 expression to promote lymphatic identity in zebrafish. Cell Rep 13, 1828-1841 https://doi.org/10.1016/j.celrep.2015.10.055
  116. Yang Y, Garcia-Verdugo JM, Soriano-Navarro M et al (2012) Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos. Blood 120, 2340-2348
  117. Hagerling R, Pollmann C, Andreas M et al (2013) A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J 32, 629-644 https://doi.org/10.1038/emboj.2012.340
  118. Karkkainen MJ, Haiko P, Sainio K et al (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5, 74-80 https://doi.org/10.1038/ni1013
  119. Semo J, Nicenboim J and Yaniv K (2016) Development of the lymphatic system: new questions and paradigms. Development 143, 924-935 https://doi.org/10.1242/dev.132431
  120. Chen H, Griffin C, Xia L and Srinivasan RS (2014) Molecular and cellular mechanisms of lymphatic vascular maturation. Microvasc Res 96, 16-22 https://doi.org/10.1016/j.mvr.2014.06.002
  121. Martinez-Corral I, Ulvmar MH, Stanczuk L et al (2015) Nonvenous origin of dermal lymphatic vasculature. Circ Res 116, 1649-1654 https://doi.org/10.1161/CIRCRESAHA.116.306170
  122. James JM, Nalbandian A and Mukouyama YS (2013) TGFβ signaling is required for sprouting lymphangiogenesis during lymphatic network development in the skin. Development 140, 3903-3914 https://doi.org/10.1242/dev.095026
  123. Petrova TV, Karpanen T, Norrmen C et al (2004) Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med 10, 974-981 https://doi.org/10.1038/nm1094
  124. Yuan L, Moyon D, Pardanaud L et al (2002) Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129, 4797-4806 https://doi.org/10.1242/dev.129.20.4797
  125. Mahamud MR, Geng X, Ho YC et al (2019) GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through miR126. Development 146, dev184218 https://doi.org/10.1242/dev.184218
  126. Srinivasan RS and Oliver G (2011) Prox1 dosage controls the number of lymphatic endothelial cell progenitors and the formation of the lymphovenous valves. Genes Dev 25, 2187-2197 https://doi.org/10.1101/gad.16974811
  127. Tammela T and Alitalo K (2010) Lymphangiogenesis: Molecular mechanisms and future promise. Cell 140, 460-476 https://doi.org/10.1016/j.cell.2010.01.045
  128. Geng X, Cha B, Mahamud MR et al (2016) Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development. Dev Biol 409, 218-233 https://doi.org/10.1016/j.ydbio.2015.10.022
  129. Geng X, Cha B, Mahamud MR and Srinivasan RS (2017) Intraluminal valves: development, function and disease. Dis Model Mech 10, 1273-1287 https://doi.org/10.1242/dmm.030825
  130. Norrmen C, Ivanov KI, Cheng J et al (2009) FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol 185, 439-457 https://doi.org/10.1083/jcb.200901104
  131. Kazenwadel J, Betterman KL, Chong CE et al (2015) GATA2 is required for lymphatic vessel valve development and maintenance. J Clin Invest 125, 2979-2994 https://doi.org/10.1172/JCI78888
  132. Danussi C, Belluz LDB, Pivetta E et al (2013) EMILIN1/α9β1 integrin interaction is crucial in lymphatic valve formation and maintenance. Mol Cell Biol 33, 4381-4394 https://doi.org/10.1128/MCB.00872-13
  133. Bazigou E, Wilson JT and Moore Jr JE (2014) Primary and secondary lymphatic valve development: molecular, functional and mechanical insights. Microvasc Res 96, 38-45 https://doi.org/10.1016/j.mvr.2014.07.008
  134. Roth Flach RJ, Guo CA, Danai LV et al (2016) Endothelial mitogen-activated protein kinase kinase kinase kinase 4 is critical for lymphatic vascular development and function. Mol Cell Biol 36, 1740-1749 https://doi.org/10.1128/MCB.01121-15