von Hippel-Lindau disease is a rare, familial genetic disease in which benign and malignant tumours grow in the kidneys and in the vasculature associated with various parts of the nervous system (in particular, the retina). The gene mutated in this disease – VHL – is a conserved E3 ubiquitin ligase that regulates angiogenesis and glycolysis by destabilising hypoxia-inducible transcription factor (HIF) under normoxic conditions. Oxygen sensing thus represents the canonical tumour suppressor function of VHL. However, in this issue, two papers provide information on the developmental roles of VHL that suggest it has other tumour suppressor functions as well.
On p. 1493, Tien Hsu, Giuseppe Gargiulo and colleagues report that VHL regulates epithelial morphogenesis during Drosophila development. The researchers generate the first genomic VHL Drosophila mutant and examine epithelial morphogenesis in the follicle cells of the egg chamber in this mutant. They show that VHL regulates the apical localisation of atypical protein kinase C (aPKC) and that this function of VHL is mediated, at least in part, by the action of VHL on microtubule stability. Without VHL function, they report, microtubules and aPKC are destabilised, which results in epithelial defects. Because loss of epithelial integrity is a crucial step in tumorigenesis, these results suggest that a potential additional tumour suppressor function for VHL is regulation of epithelial morphogenesis.
On p. 1563, Toshio Suda, Hideyuki Okano and colleagues report that VHL regulates the fetal to adult retinal circulatory system transition in mice. After birth, the hyaloid vessels that circulate blood in the neonatal retina are replaced by retinal vessels in a process that is mediated by macrophages. But could the dramatic change in the oxygen environment that occurs at birth also be involved in this transition? To find out, the researchers generate retina-specific VHL conditional-knockout mice and show that the fetal to adult retinal circulatory system transition is arrested in these animals. This arrest can be rescued by local VEGF inhibition or by genetic inhibition of HIF-1α. Thus, VHL-mediated oxygen-sensing mechanisms help to regulate the development of the adult circulatory system in the retina, a finding that might explain why retinal angiomas are a common characteristic of VHL disease.