Tracheal morphogenesis and the Drosophila von Hippel-Lindau tumor suppressor gene. B. Adryan 1,2, H.J.H. Decker 2, T. Hsu 1. 1) Center for Molecular & Structural Biology, Medical University of South Carolina, Charleston, SC; 2) Department of Hematology and Oncology, University of Mainz, Germany.
Germline mutations in the von Hippel-Lindau tumor suppressor gene (VHL) and somatic inactivation of the other allele result in highly vascularized tumors such as clear cell renal carcinoma, retinal angioma, and hemangioblastomas of the central nervous system. It has been suggested that VHL, together with elongin B/C, cullin-2 and Rbx1, forms an E3 ubiquitin ligase complex. In this capacity, VHL is believed to down-regulate several pro-vascularization factors, including the a subunit of the hypoxia-inducible factor 1 (Hif-1a). Hif-1 is a transcription activator that mediates the hypoxia-induced up-regulation of the vascular endothelial growth factor (VEGF) expression. These documented VHL functions can therefore explain the over-vascularized phenotypes in the VHL tumors. However, germline VHL knockout mice showed embryonic lethality due to a lack of vascularization in the placenta. In an attempt to resolve this apparent contradiction, we sought to study the VHL function in an experimentally accessible in vivo system, Drosophila melanogaster. The Drosophila VHL gene (d-vhl) is cloned. It shows high degree of conservation when compared with other VHL proteins from human and C. elegans. The gene is mapped to chromosomal position 47E1-3. During embryogenesis, d-vhl is expressed in the developing tracheal regions where tube outgrowth no longer occur. d-vhl loss-of-function mutants (induced by RNA interference) showed ectopic branching and looping accompanied by breakage in the main trunk, whereas gain-of-function embryos showed a general lack of vasculature. Importantly, over-expression of the human VHL in flies can induce the same gain-of-function phenotype. We suggest that d-vhl is required for halting cell migration and tube outgrowth at the end of the tracheal tube formation.