The role of the mir-310s in Hedgehog Signaling regulation under dietary stress in the Drosophila ovary

The role of the mir-310s in Hedgehog Signaling regulation under dietary stress in the Drosophila ovary

Çiçek, Ibrahim Ömer

Dissertation

Angenommen am: 2015-05-22

Erschienen: 2016-02-03

Betreuer: Shcherbata, Halyna PD Dr.

Gutachter: Dosch, Roland Dr.

Gutachter: Wodarz, Andreas Prof. Dr.

Zum Verlinken/Zitieren: http://hdl.handle.net/11858/00-1735-0000-0028-86B2-A

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Name: CICEK I Omer Doctoral Thesis.pdf

Größe: 4,6 MB

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Zusammenfassung

Englisch

Perturbations in nutrition and energy homeostasis can have deleterious effects on human health. Therefore, mechanisms controlling metabolic balance and initiating fast response to changing dietary conditions are essential. Such fast and robust responses at the cellular level can be achieved by microRNA (miRNA) mediated control of gene expression. In this study, the mir-310s are shown as important controllers of metabolic status of Drosophila. The mir-310s mutants have numerous starvation-sensitive genes deregulated at the protein and mRNA levels and exhibit diet-sensitive physiological phenotypes, such as low fecundity and high body fat accumulation. Moreover, the mir-310s regulate Hedgehog (Hh) signaling by targeting three Hh pathway-associated genes (Rab23, DHR96, and ttk), linking the egg production with the dietary status. In the ovary, this regulation is essential to tune the Hh signaling strength, which has to be kept at low levels under nutritional restriction. Here, Drosophila Rab23 is identified as a novel positive regulatory element of Hh signaling. Rab23 is shown to act cell-autonomously, regulating Hh ligand release by facilitating its intracellular mobility. These findings shed light on miRNA-based control of the Hh pathway in a nutrition-sensitive context. From flies to humans, the conservation of mir-310s seed sequences, Rab23, and Hh signaling raises the possibility that this control mechanism is existing in humans as well. Therefore, these findings are important for the better understanding of metabolic diseases and development of miRNA related therapeutics.

Keywords: Drosophila melanogaster; miRNA; diet; Rab23; Hedgehog signaling