THE DROSOPHILA HOMOLOGUE OF THE HUMAN VON HIPPEL-LINDAU TUMOR SUPPRESSOR GENE IS REQUIRED FOR EPITHELIAL INTEGRITY OF FOLLICLE CELLS

The tumour suppressor gene product pVHL (Von-Hippel Lindau protein) is implicated in a variety of processes including ubiquitination of the alpha subunit of HIF (hypoxia-inducible factor), cell-cycle control, differentiation, extracellular matrix formation and turnover, and angiogenesis. However, the developmental function of VHL gene has not been fully understood. It was shown previously that Drosophila VHL (d-VHL) down-regulates the motility of tubular epithelial cells (tracheal cells). To examine whether d-VHL has a more general role in epithelial morphogenesis, we analyzed the follicle cell phenotype produced by loss-of-function d-VHL mutation. Homozygous d-VHL clones, genetically marked by the absence of GFP, were obtained through somatic recombination using the FLP/FRT system. Loss of d-VHL function causes a cell autonomous effect on epithelial integrity of the follicle cells, including multilayering and altered cell shape. Strong propidium iodide (nuclear) staining was also observed, indicating possible dysregulation of endocycles. The analysis of epithelial junction protein patterns such as Discs-large, atypical-Protein Kinase C and Crumbs showed that loss of d-VHL function causes altered distribution or absence of these proteins in follicular epithelium. These abnormal epithelial characteristics are associated with detachment from the basement membrane. This is interesting since integrin-mediated basal attachment is presumably the initial step in epithelial morphogenesis. Besides integrin, we have shown that abnormal wing discs (awd) gene, the Drosophila homolog of human nucleotide diphosphate kinase nm23H1, is localized to the basal domain. Interestingly, d-VHL loss of function clones showed strong reduction of awd gene expression. We propose that d-VHL may be a novel epithelial morphogenic factor that promotes the stability of the basal attachment complex.