Cell autonomy of HIF effects in Drosophila: tracheal cells sense hypoxia and induce terminal branch sprouting.
Drosophila tracheal terminal branches are plastic and have the capacity to sprout out projections toward oxygen-starved areas, in a process analogous to mammalian angiogenesis. This response involves the upregulation of FGF/Branchless in hypoxic tissues, which binds its receptor Breathless on tracheal cells. Here, we show that extra sprouting depends on the Hypoxia-Inducible Factor (HIF)-alpha homolog Sima and on the HIF-prolyl hydroxylase Fatiga that operates as an oxygen sensor. In mild hypoxia, Sima accumulates in tracheal cells, where it induces breathless, and this induction is sufficient to provoke tracheal extra sprouting. In nontracheal cells, Sima contributes to branchless induction, whereas overexpression of Sima fails to attract terminal branch outgrowth, suggesting that HIF-independent 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 Branchless levels, and that this mechanism is a cardinal step in hypoxia-dependent tracheal sprouting.
Centanin
Lázaro
L
Instituto Leloir and FBMC, FCEyN-Universidad de Buenos Aires, CONICET, Patricias Argentinas 435, Buenos Aires 1405, Argentina.
Dekanty
Andrés
A
Romero
Nuria
N
Irisarri
Maximiliano
M
Gorr
Thomas A
TA
Wappner
Pablo
P
D000818:Animals; D019521:Body Patterning; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007814:Larva / Q000033:anatomy & histology; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017468:Receptors, Fibroblast Growth Factor; C100429:Sima protein, Drosophila; C102644:bnl protein, Drosophila; D005346:Fibroblast Growth Factors; C491512:Hif prolyl hydroxylase, Drosophila; D011393:Procollagen-Proline Dioxygenase; C102301:BTL protein, Drosophila; D011505:Protein-Tyrosine Kinases; D010100:Oxygen