Autonomous Tracheal Sprouting

Abstract

Hypoxia-inducible factor (HIF) signaling is important for regulating the oxidative stress response as well as for branching morphogenesis of tubular oxygen-delivering tissues such as vertebrate blood vessels. Centanin et al . investigated the role of Similar (Sima), a homolog of the transcription factor HIF-α, and its repressor Fatiga (Fga) in Drosophila tracheal development. Under normal oxygen conditions, Sima is marked for degradation by Fga-mediated hydroxylation; under hypoxic conditions, this oxygen-dependent reaction slows and Sima accumulates, stimulating transcription of hypoxia-inducible genes. Trachea of fga loss-of-function mutants sprouted more branches than wild-type trachea, and overexpression of sima in the trachea, but not in tissues surrounding the trachea, was sufficient to induce extra branching. sima loss-of-function mutants, however, had wild-type tracheal branching when reared in normoxic conditions. Under hypoxic conditions, sima induced expression of the fibroblast growth factor (FGF) receptor breathless ( btl ) in trachea and the FGF branchless ( bnl ) in tissue around the trachea. In normal development, Btl and Bnl are essential for tracheal branching: btl -expressing tracheal cells are attracted to target tissues that secrete Bnl. These data suggest that all aspects of Drosophila tracheal branching are genetically programmed but that under hypoxic conditions the HIF pathway stimulates extra tracheal branching via the well-characterized Btl/Bnl chemoattraction system. Thus, the Sima-Fga oxygen sensor is required in both trachea and surrounding tissues for hypoxia-induced branching, and the trachea may initiate branching independently of signaling from the target tissue. L. Centanin, A. Dekanty, N. Romero, M. Irisarri, T. A. Gorr, P. Wappner, Cell autonomy of HIF effects in Drosophila : Tracheal cells sense hypoxia and induce terminal branch sprouting. Dev. Cell 14 , 547-558 (2008). [PubMed]