Glycan glucuronylation is an essential glycan modification for female fertility in drosophila melanogaster
Waltamath, Marion Elizabeth
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The Drosophila melanogaster is a dynamic organism to study how tissue specific glycosylation during development. Drosophila O-linked glycans are frequently capped with glucuronic acid. In order to understand the potential functions of glycan glucuronylation in Drosophila, we generated a mutation in a glucuronyltransferase, GlcAT-S (GlcAT-Scms), that results in adult female infertility and a significant decrease in the prevalence of glucuronylated O-glycans. GlcAT-Scms females are infertile due to ovaries that fail to mature past early stages and subsequently do not produce embryos. Mutant ovaries are characterized by mislocalization of the oocyte and an over-proliferation of undifferentiated follicle cells. Both Notch and Hedgehog signaling pathways play significant roles in the proper development of the ovary. In GlcAT-Scms mutants, the Notch signaling pathway is upregulated earlier in the germarium; however, mutant ovary phenotypes are not consistent with overexpression of the Notch pathway and are instead a result of disruption of the Notch pathway feedback loop. These phenotypes are more consistent with mutations in the Hedgehog (Hh) pathway that result in constitutive Hh signaling. GlcAT-Scms ovaries have an increased amount of Hh corresponds to the increased activation on the pathway. This increase of Hedgehog and subsequent upregulation of the pathway corresponds not to an overexpression of Hedgehog but an increase in forms of Hedgehog called undisruptible because of their resistance to degradation by boiling, denaturants and reducing agents.. These undisruptible Hedgehog multimers are generated by the activity of transglutaminase. Hedgehog contains three putative O-glycosylation sites very near to the key residues involved in the transglutaminase reaction. We therefore propose a model where the presence of neighboring glucuronylated O-glycans causes steric hindrance that normally limits the action of transglutaminase to covalently link Hh monomers. These findings reveal the importance of proper glycan glucuronlyation for critical signaling and maturation of the ovary.