S12-04 Cell cycle regulation of a Wnt receptor

Drosophila tracheal terminal branches are plastic and have the capacity to sprout-out projections towards oxygen-starved areas, in a process analogous to mammalian angiogenesis. It was previously shown that this sprouting response involves the upregulation of the FGF homolog Branchless in hypoxic tissues, which binds its receptor Breathless on tracheal cells, thereby attracting the outgrowth of terminal cells. We have found that tracheal extra-sprouting depends on the Hypoxia Inducible Factor alphasubunit Sima, as well as on the HIF prolyl hydroxylase Fatiga that operates as an oxygen sensor. In mild hypoxia, Sima accumulates mainly in tracheal terminal cells, where it promotes transcriptional upregulation of the receptor breathless. Strikingly, this induction is sufficient to provoke extra-sprouting of tracheal terminal branches. In non-tracheal cells, Sima contributes to induction of the ligand branchless, whilst over-expression of Sima fails on itself to attract terminal branch outgrowth, suggesting that HIFindependent components are also required for full induction of the ligand. We propose that the autonomous response to hypoxia that occurs in tracheal cells enhances tracheal sensitivity to increasing levels of the ligand Branchless, and that this mechanism is a cardinal step in hypoxia-dependent tracheal sprouting.