Editors' ChoiceDevelopment

Noncanonical Notch in Normoxia

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Sci. Signal.  07 Jun 2011:
Vol. 4, Issue 176, pp. ec158
DOI: 10.1126/scisignal.4176ec158

Crystal cells are platelet-like cells that mediate clotting and wound healing in the fruit fly Drosophila melanogaster, and their specification and maintenance require Notch signaling. Mukherjee et al. report that Sima, the fly ortholog of hypoxia-inducible factor-α (HIF-α), was present in crystal cells even under normoxic conditions and was also required for crystal cell maintenance. Altering the abundance of Sima in the lymph gland, the site of crystal cell production, resulted in phenotypes similar to corresponding loss or gain of Notch signaling, and heterozygosity for a mutation sima (sima+/–) suppressed Notch-driven overproduction of crystal cells. Sima was required for maintenance of crystal cells because transgenic expression of either a sima RNA interference (RNAi) construct or a transgene encoding the hydroxy prolyl hydroxylase Hph, which tags Sima for degradation, in late-stage crystal cell precursors caused them to burst. Both Notch and its ligand Serrate (Ser) were required for specification of crystal cells, but only Notch and Sima were required for survival of crystal cells. Full-length Notch, which can accumulate in endosomes in the absence of ligand, colocalized with Sima in endosomes. Sima’s binding partner Tango (Tgo; the ortholog of HIF-β) was not required for crystal cell specification, nor was a hypoxia-induced reporter expressed in crystal cells, indicating that the function of Sima in this context did not require prototypical hypoxic signaling. However, reducing Tgo by RNAi or stabilizing Sima (by blocking Hph activity or exposing larvae to hypoxia) increased the production of crystal cells, suggesting that its interaction with Tgo may prevent Sima from interacting with Notch. Reducing the abundance of nitric oxide (NO), which stabilizes Sima under normoxic conditions, in mature crystal cells by means of NO synthase 1 (NOS1) RNAi caused the cells to burst, and feeding larvae an NO inhibitor reduced Notch reporter activation. These results suggest a model in which NO stabilizes Sima, which interacts with full-length Notch to promote crystal cell specification and maintenance. It had been demonstrated previously that HIF-α and Notch interact directly in hypoxic signaling, and this study identifies a context in which HIF-α may promote Notch signaling independent of hypoxia and Notch ligands.

T. Mukherjee, W. S. Kim, L. Mandal, U. Banerjee, Interaction between Notch and Hif-α in development and survival of Drosophila blood cells. Science 332, 1210–1213 (2011). [Abstract] [Full Text]