VEGFR3 gene structure, regulatory region, and sequence polymorphisms

Vascular endothelial growth factor receptor 3 (VEGFR-3) is required for car diovascular development during embryogenesis. In adults, this receptor is e xpressed in lymphatic endothelial cells, and mutant VEGFR3 alleles have bee n implicated in human hereditary lymphedema. To better understand the basis of its specific endothelial lineage-restricted expression, we have charact erized the I VEGFR3 gene and its regulatory 5' flanking region. The human g ene contains 31 exons, of which exons 30a and 30b are alternatively spliced . The VEGFR3 proximal promoter is TATA-less and contains stretches of seque nces homologous with the mouse Vegfr3 promoter region. In transfection expe riments of cultured cells, the Vegfr3 promoter was shown to control endothe lial 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 expressi on of the LacZ marker gem. This suggests that endothelial cell-specific ele ments occur in the proximal promoter, although further enhancer elements ar e probably located elsewhere. The sequence, organization, and variation in the VEGFR3 gene and its regulatory region provide important tools for the m olecular genetic analysis of the lymphatic system and its disorders.