miR-125 regulates niche organization in Drosophila melanogaster ovary by affecting Notch signaling pathway via its target Tom

miR-125 regulates niche organization in Drosophila melanogaster ovary by affecting Notch signaling pathway via its target Tom

Berenike Johanna Bögeholz

Doctoral thesis

Date of Examination: 2015-08-19

Date of issue: 2015-08-11

Advisor: Dobbelstein, Matthias Prof. Dr.

Referee: Pieler, Tomas Prof. Dr.

Referee: Schön, Margarete Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0022-6074-0

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Abstract

English

For the maintenance of tissue homeostasis upon injury or natural cell turnover, a constant source of new cells is needed. Usually these cells are delivered by tissue specific adult stem cells. The stem cells reside in a specialized microenvironment, called the niche. This niche provides an environment controlling adult stem cell proliferation and maintenance. Defects in the formation of the niche may result in stem cell loss or overproliferation, and can lead to a l ack of tissue regeneration or cancer formation. A better understanding of stem cells in their natural environment may help to understand the development of certain diseases, such as cancer, and may change their treatment. Previously, microRNAs were shown to participate in stem cell regulation in vivo. This study investigated the role of microRNA miR-125 (part of the conserved let-7-Complex) in the Drosophila melanogaster germarium. The Drosophila germarium hosts germline stem cells (GSCs) and is an ideal model system to study the interaction between stem cells and their niche. In this study, we show that miR-125 participates in the establishment of proper GSC niche. Strikingly, the GSC niche was expanded upon loss or overexpression of miR-125 and hosted an increased number of stem cells. This developmental niche expansion upon aberrant miR-125 levels shows similarities to the proposed expansion of ‘precancer niches’ promoting the formation and progression of mammalian tumors. We have found that miR-125 targets Tom, a member of the Bearded family, involved in the regulation of the highly conserved Notch pathway. As the transcription of miR-125 is triggered by ecdysone, a steroid hormone in the fly, miR-125 can be proposed as a linkage between steroid hormones and the prominent Notch pathway. Thus, miR-125 may help to regulate Notch signaling spatially and temporally.

Keywords: miRNA; Drosophila melanogaster; Notch-Pathway; miR-125; stem cell; niche