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Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland;
* Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA; and
A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland
1Correspondence: Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute, University of Helsinki, P.O.B. 21, Haartmaninkatu 3, 00014 Helsinki, Finland. E-mail: Kari.Alitalo{at}Helsinki.FI
Vascular endothelial growth factor receptor 3 (VEGFR-3) is required for cardiovascular development during embryogenesis. In adults, this receptor is expressed in lymphatic endothelial cells, and mutant VEGFR3 alleles have been implicated in human hereditary lymphedema. To better understand the basis of its specific endothelial lineage-restricted expression, we have characterized the VEGFR3 gene and its regulatory 5' flanking region. The human gene contains 31 exons, of which exons 30a and 30b are alternatively spliced. The VEGFR3 proximal promoter is TATA-less and contains stretches of sequences homologous with the mouse Vegfr3 promoter region. In transfection experiments of cultured cells, the Vegfr3 promoter was shown to control endothelial cell-specific transcription of downstream reporter genes. This result was further confirmed in vivo; in a subset of transgenic mouse embryos, a 1.6 kb Vegfr3 promoter fragment directed weak lymphatic endothelial expression of the LacZ marker gene. This suggests that endothelial cell-specific elements occur in the proximal promoter, although further enhancer elements are probably located elsewhere. The sequence, organization, and variation in the VEGFR3 gene and its regulatory region provide important tools for the molecular genetic analysis of the lymphatic system and its disorders.—Iljin, K., Karkkainen, M. J., Lawrence, E. C., Kimak, M. A., Uutela, M., Taipale, J., Pajusola, K., Alhonen, L., Halmekytö, M., Finegold, D. N., Ferrell, R. E., Alitalo, K. VEGFR3 gene structure, regulatory region, and sequence polymorphisms.
Key Words: FLT4 • receptor tyrosine kinase • promoter • endothelial cell • lymphangiogenesis
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