Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. 1995 Apr 11; 92(8): 3566–3570.

Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development.


We have recently cloned the human fms-like tyrosine kinase 4 gene FLT4, whose protein product is related to two vascular endothelial growth factor receptors FLT1 and KDR/FLK1. Here the expression of FLT4 has been analyzed by in situ hybridization during mouse embryogenesis and in adult human tissues. The FLT4 mRNA signals first became detectable in the angioblasts of head mesenchyme, the cardinal vein, and extraembryonally in the allantois of 8.5-day postcoitus (p.c.) embryos. In 12.5-day p.c. embryos, the FLT4 signal decorated developing venous and presumptive lymphatic endothelia, but arterial endothelia were negative. During later stages of development, FLT4 mRNA became restricted to vascular plexuses devoid of red cells, representing developing lymphatic vessels. Only the lymphatic endothelia and some high endothelial venules expressed FLT4 mRNA in adult human tissues. Increased expression occurred in lymphatic sinuses in metastatic lymph nodes and in lymphangioma. Our results suggest that FLT4 is a marker for lymphatic vessels and some high endothelial venules in human adult tissues. They also support the theory on the venous origin of lymphatic vessels.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.8M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992 Jun 5;267(16):10931–10934. [PubMed]
  • Pardanaud L, Altmann C, Kitos P, Dieterlen-Lievre F, Buck CA. Vasculogenesis in the early quail blastodisc as studied with a monoclonal antibody recognizing endothelial cells. Development. 1987 Jun;100(2):339–349. [PubMed]
  • Coffin JD, Poole TJ. Embryonic vascular development: immunohistochemical identification of the origin and subsequent morphogenesis of the major vessel primordia in quail embryos. Development. 1988 Apr;102(4):735–748. [PubMed]
  • Flamme I, Risau W. Induction of vasculogenesis and hematopoiesis in vitro. Development. 1992 Oct;116(2):435–439. [PubMed]
  • Noden DM. Embryonic origins and assembly of blood vessels. Am Rev Respir Dis. 1989 Oct;140(4):1097–1103. [PubMed]
  • Gonzalez-Crussi F. Vasculogenesis in the chick embryo. An ultrastructural study. Am J Anat. 1971 Apr;130(4):441–460. [PubMed]
  • Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987 Jan 23;235(4787):442–447. [PubMed]
  • Klagsbrun M, D'Amore PA. Regulators of angiogenesis. Annu Rev Physiol. 1991;53:217–239. [PubMed]
  • van der Putte SC. The development of the lymphatic system in man. Adv Anat Embryol Cell Biol. 1975;51(1):3–60. [PubMed]
  • Hobson B, Denekamp J. Endothelial proliferation in tumours and normal tissues: continuous labelling studies. Br J Cancer. 1984 Apr;49(4):405–413. [PMC free article] [PubMed]
  • Folkman J. The role of angiogenesis in tumor growth. Semin Cancer Biol. 1992 Apr;3(2):65–71. [PubMed]
  • de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. [PubMed]
  • Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Böhlen P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579–1586. [PubMed]
  • Millauer B, Wizigmann-Voos S, Schnürch H, Martinez R, Møller NP, Risau W, Ullrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993 Mar 26;72(6):835–846. [PubMed]
  • Pajusola K, Aprelikova O, Korhonen J, Kaipainen A, Pertovaara L, Alitalo R, Alitalo K. FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer Res. 1992 Oct 15;52(20):5738–5743. [PubMed]
  • Pajusola K, Aprelikova O, Pelicci G, Weich H, Claesson-Welsh L, Alitalo K. Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors. Oncogene. 1994 Dec;9(12):3545–3555. [PubMed]
  • Finnerty H, Kelleher K, Morris GE, Bean K, Merberg DM, Kriz R, Morris JC, Sookdeo H, Turner KJ, Wood CR. Molecular cloning of murine FLT and FLT4. Oncogene. 1993 Aug;8(8):2293–2298. [PubMed]
  • Tokunaga K, Taniguchi H, Yoda K, Shimizu M, Sakiyama S. Nucleotide sequence of a full-length cDNA for mouse cytoskeletal beta-actin mRNA. Nucleic Acids Res. 1986 Mar 25;14(6):2829–2829. [PMC free article] [PubMed]
  • Kaipainen A, Korhonen J, Pajusola K, Aprelikova O, Persico MG, Terman BI, Alitalo K. The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. J Exp Med. 1993 Dec 1;178(6):2077–2088. [PMC free article] [PubMed]
  • Korhonen J, Partanen J, Armstrong E, Vaahtokari A, Elenius K, Jalkanen M, Alitalo K. Enhanced expression of the tie receptor tyrosine kinase in endothelial cells during neovascularization. Blood. 1992 Nov 15;80(10):2548–2555. [PubMed]
  • van Hinsbergh VW, Binnema D, Scheffer MA, Sprengers ED, Kooistra T, Rijken DC. Production of plasminogen activators and inhibitor by serially propagated endothelial cells from adult human blood vessels. Arteriosclerosis. 1987 Jul-Aug;7(4):389–400. [PubMed]
  • Van Hinsbergh VW, Sprengers ED, Kooistra T. Effect of thrombin on the production of plasminogen activators and PA inhibitor-1 by human foreskin microvascular endothelial cells. Thromb Haemost. 1987 Apr 7;57(2):148–153. [PubMed]
  • Bonthron D, Orr EC, Mitsock LM, Ginsburg D, Handin RI, Orkin SH. Nucleotide sequence of pre-pro-von Willebrand factor cDNA. Nucleic Acids Res. 1986 Sep 11;14(17):7125–7127. [PMC free article] [PubMed]
  • Partanen J, Armstrong E, Mäkelä TP, Korhonen J, Sandberg M, Renkonen R, Knuutila S, Huebner K, Alitalo K. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol. 1992 Apr;12(4):1698–1707. [PMC free article] [PubMed]
  • Shi E, Kan M, Xu JM, McKeehan WL. 16-kilodalton heparin binding (fibroblast) growth factor type one appears in a stable 40-kilodalton complex after receptor-dependent internalization. J Biol Chem. 1991 Mar 25;266(9):5774–5779. [PubMed]
  • Cattoretti G, Becker MH, Key G, Duchrow M, Schlüter C, Galle J, Gerdes J. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992 Dec;168(4):357–363. [PubMed]
  • Korhonen J, Polvi A, Partanen J, Alitalo K. The mouse tie receptor tyrosine kinase gene: expression during embryonic angiogenesis. Oncogene. 1994 Feb;9(2):395–403. [PubMed]
  • Sato TN, Qin Y, Kozak CA, Audus KL. Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9355–9358. [PMC free article] [PubMed]
  • Pajusola K, Aprelikova O, Armstrong E, Morris S, Alitalo K. Two human FLT4 receptor tyrosine kinase isoforms with distinct carboxy terminal tails are produced by alternative processing of primary transcripts. Oncogene. 1993 Nov;8(11):2931–2937. [PubMed]
  • Peters K, Ornitz D, Werner S, Williams L. Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev Biol. 1993 Feb;155(2):423–430. [PubMed]
  • Zadvinskis DP, Benson MT, Kerr HH, Mancuso AA, Cacciarelli AA, Madrazo BL, Mafee MF, Dalen K. Congenital malformations of the cervicothoracic lymphatic system: embryology and pathogenesis. Radiographics. 1992 Nov;12(6):1175–1189. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    NCBI Bookshelf books that cite the current articles.
  • Gene
    Gene records that cite the current articles. Citations in Gene are added manually by NCBI or imported from outside public resources.
  • GEO Profiles
    GEO Profiles
    Gene Expression Omnibus (GEO) Profiles of molecular abundance data. The current articles are references on the Gene record associated with the GEO profile.
  • HomoloGene
    HomoloGene clusters of homologous genes and sequences that cite the current articles. These are references on the Gene and sequence records in the HomoloGene entry.
  • MedGen
    Related information in MedGen
  • OMIM
    Genome Survey Sequence (GSS) nucleotide records reported in the current articles.
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...