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Prox1, master regulator of the lymphatic vasculature phenotype

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Abstract

In contrast to the extensive molecular and functional characterization of blood vascular endothelium, little is known about the mechanisms that control the formation and lineage-specific differentiation and function of lymphatic vessels. The homeobox gene Prox1, the vertebrate homologue of the Drosophila prospero gene, has been recently identified to be required for the induction of lymphatic vascular development from preexisting embryonic veins, and studies in Prox1-deficient mice have confirmed Florence Sabin's original hypothesis about the origin of the lymphatic vascular system from embryonic veins. The recent establishment of cell culture models for the selective propagation of blood vascular and lymphatic endothelial cells, together with the findings that these cells maintain their lineage-specific differentiation in vitro, has led to the discovery that Prox1 expression is sufficient to induce a lymphatic phenotype in blood vascular endothelium. Ectopic expression of Prox1 downregulated blood vascular-associated genes and also upregulated some of the known lymphatic endothelial cell markers. Together, these studies suggest that the blood vascular phenotype represents the default endothelial differentiation and they identify an essential role of Prox1 in the program specifying lymphatic endothelial cell fate.

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References

  • Asellius G (1627) De lactibus sive lacteis venis. Mediolani, Milan

  • Chu-Lagraff Q, Wright DM, McNeil LK, Doe CQ (1991) The prospero gene encodes a divergent homeodomain protein that controls neuronal identity in Drosophila. Development Suppl:79–85

    Google Scholar 

  • Demidenko Z, Badenhorst P, Jones T, Bi X, Mortin MA (2001) Regulated nuclear export of the homeodomain transcription factor Prospero. Development 128:1359-1367

    CAS  PubMed  Google Scholar 

  • Doe CQ (1992) Molecular markers for identified neuroblasts and ganglion mother cells in the Drosophila central nervous system. Development 116:855–863

    CAS  PubMed  Google Scholar 

  • Doe CQ, Chu-LaGraff Q, Wright DM, Scott MP (1991) The prospero gene specifies cell fates in the Drosophila central nervous system. Cell 65:451–464

    CAS  PubMed  Google Scholar 

  • Duncan MK, Cui W, Oh DJ, Tomarev SI (2002) Prox1 is differentially localized during lens development. Mech Dev 112:195–198

    Article  CAS  PubMed  Google Scholar 

  • Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT (1998) A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci U S A 95:258–263

    Article  CAS  PubMed  Google Scholar 

  • Hassan B, Li L, Bremer KA, Chang W, Pinsonneault J, Vaessin H (1997) Prospero is a panneural transcription factor that modulates homeodomain protein activity. Proc Natl Acad Sci U S A 94:10991–10996

    Article  CAS  PubMed  Google Scholar 

  • Hirakawa S, Hong YK, Harvey N, Schacht V, Matsuda K, Libermann T, Detmar M (2003) Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol 162:575–586

    CAS  PubMed  Google Scholar 

  • Hirata J, Nakagoshi H, Nabeshima Y, Matsuzaki F (1995) Asymmetric segregation of the homeodomain protein Prospero during Drosophila development. Nature 377:627–630

    Article  CAS  PubMed  Google Scholar 

  • Hong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, Detmar M, Oliver G (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 225:351–357

    Article  CAS  PubMed  Google Scholar 

  • Huntington GS, McClure CFW (1910) The anatomy and development of the jugular lymph sac in the domestic cat (Felis domestica). Am J Anat 10:177–311

    Google Scholar 

  • Jackson DG, Prevo R, Clasper S, Banerji S (2001) LYVE-1, the lymphatic system and tumor lymphangiogenesis. Trends Immunol 22:317–321

    Article  CAS  PubMed  Google Scholar 

  • Jacobs JR (1993) Perturbed glial scaffold formation precedes axon tract malformation in Drosophila mutants. J Neurobiol 24:611–626

    CAS  PubMed  Google Scholar 

  • Jan YN, Jan LY (1998) Asymmetric cell division. Nature 392:775–778

    Article  CAS  PubMed  Google Scholar 

  • Kaipainen A, Korhonen J, Mustonen T, van HV, Fang GH, Dumont D, Breitman M, Alitalo K (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 92:3566–3570

    CAS  PubMed  Google Scholar 

  • Kauffmann RC, Li S, Gallagher PA, Zhang J, Carthew RW (1996) Ras1 signaling and transcriptional competence in the R7 cell of Drosophila. Genes Dev 10:2167–2178

    CAS  PubMed  Google Scholar 

  • Knoblich JA, Jan LY, Jan YN (1995) Asymmetric segregation of Numb and Prospero during cell division. Nature 377:624–627

    Article  CAS  PubMed  Google Scholar 

  • Kriehuber E, Breiteneder GS, Groeger M, Soleiman A, Schoppmann SF, Stingl G, Kerjaschki D, Maurer D (2001) Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med 194:797–808

    CAS  PubMed  Google Scholar 

  • Li L, Vaessin H (2000) Pan-neural Prospero terminates cell proliferation during Drosophila neurogenesis. Genes Dev 14:147–151

    CAS  PubMed  Google Scholar 

  • Maekinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K (2001) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20:4762–4773

    Article  CAS  PubMed  Google Scholar 

  • Manning L, Doe CQ (1999) Prospero distinguishes sibling cell fate without asymmetric localization in the Drosophila adult external sense organ lineage. Development 126:2063–2071

    CAS  PubMed  Google Scholar 

  • Matsuzaki F, Koizumi K, Hama C, Yoshioka T, Nabeshima Y (1992) Cloning of the Drosophila prospero gene and its expression in ganglion mother cells. Biochem Biophys Res Commun 182:1326–1332

    CAS  PubMed  Google Scholar 

  • Myster DL, Duronio RJ (2000) To differentiate or not to differentiate? Curr Biol 10:R302–304

    Google Scholar 

  • Oliver G, 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

    Article  CAS  PubMed  Google Scholar 

  • Oliver G, Sosa-Pineda B, Geisendorf S, Spana EP, Doe CQ, Gruss P (1993) Prox 1, a prospero-related homeobox gene expressed during mouse development. Mech Dev 44:3–16

    CAS  PubMed  Google Scholar 

  • Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K (2002) Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21:4593–4599

    Article  CAS  PubMed  Google Scholar 

  • Podgrabinska S, Braun P, Velasco P, Kloos B, Pepper MS, Jackson DG, Skobe M (2002) Molecular characterization of lymphatic endothelial cells. Proc Natl Acad Sci U S A 99:16069–16074

    Article  CAS  PubMed  Google Scholar 

  • Rusznyak I, Foeldi M, Szabo G (1967) Lymphatics and lymph circulation. Pergamon, Oxford

  • Sabin FR (1902) On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. Am J Anat 1:367–391

    Google Scholar 

  • Sabin FR (1904) On the development of the superficial lymphatics in the skin of the pig. Am J Anat 3:183–195

    Google Scholar 

  • Schaefer JJ, Oliver G, Henry JJ (1999) Conservation of gene expression during embryonic lens formation and cornea-lens transdifferentiation in Xenopus laevis. Dev Dyn 215:308–318

    Article  CAS  PubMed  Google Scholar 

  • Schneider M, Othman-Hassan K, Christ B, Wilting J (1999) Lymphangioblasts in the avian wing bud. Dev Dyn 216:311–319

    Article  CAS  PubMed  Google Scholar 

  • Skobe M, Detmar M (2000) Structure, function and molecular control of the skin lymphatic system. J Invest Dermatol Symp Proc 5:14–19

    Article  CAS  Google Scholar 

  • Sosa-Pineda B, Wigle JT, Oliver G (2000) Hepatocyte migration during liver development requires Prox1. Nat Genet 25:254–255

    Article  CAS  PubMed  Google Scholar 

  • Spana EP, Doe CQ (1995) The prospero transcription factor is asymmetrically localized to the cell cortex during neuroblast mitosis in Drosophila. Development 121:3187–3195

    CAS  PubMed  Google Scholar 

  • Tomarev SI, Sundin O, Banerjee-Basu S, Duncan MK, Yang JM, Piatigorsky J (1996) Chicken homeobox gene Prox 1 related to Drosophila prospero is expressed in the developing lens and retina. Dev Dyn 206:354–367

    Article  CAS  PubMed  Google Scholar 

  • Tomarev SI, Zinovieva RD, Chang B, Hawes NL (1998) Characterization of the mouse Prox1 gene. Biochem Biophys Res Commun 248:684–689

    Article  CAS  PubMed  Google Scholar 

  • Vaessin H, Grell E, Wolff E, Bier E, Jan LY, Jan YN (1991) Prospero is expressed in neuronal precursors and encodes a nuclear protein that is involved in the control of axonal outgrowth in Drosophila. Cell 67:941–953

    CAS  PubMed  Google Scholar 

  • Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778

    CAS  PubMed  Google Scholar 

  • Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, Jackson DG, Oliver G (2002) An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 21:1505–1513

    Article  CAS  PubMed  Google Scholar 

  • Wilting J (2001) New perspectives in lymphangiogenesis research. Microsc Res Tech 55:59–60

    Article  CAS  PubMed  Google Scholar 

  • Wilting J, Papoutsi M, Othman-Hassan K, Rodriguez-Niedenfuhr M, Prols F, Tomarev SI, Eichmann A (2001) Development of the avian lymphatic system. Microsc Res Tech 55:81–91

    Article  CAS  PubMed  Google Scholar 

  • Witte MH, Bernas MJ, Martin CP, Witte CL (2001) Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology. Microsc Res Tech 55:122–145

    Article  CAS  PubMed  Google Scholar 

  • Zinovieva RD, Duncan MK, Johnson TR, Torres R, Polymeropoulos MH, Tomarev SI (1996) Structure and chromosomal localization of the human homeobox gene Prox 1. Genomics 35:517–522

    Article  CAS  PubMed  Google Scholar 

Download references

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Authors and Affiliations

  1. Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Young-Kwon Hong & Michael Detmar

  2. Cutaneous Biology Research Center, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA

    Young-Kwon Hong

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  1. Young-Kwon Hong
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  2. Michael Detmar
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Correspondence to Young-Kwon Hong.

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Hong, YK., Detmar, M. Prox1, master regulator of the lymphatic vasculature phenotype. Cell Tissue Res 314, 85–92 (2003). https://doi.org/10.1007/s00441-003-0747-8

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  • DOI: https://doi.org/10.1007/s00441-003-0747-8

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