Ecdysone signaling and miRNA let-7 cooperate in regulating the differentiation of the germline stem cell progeny
by Annekatrin König
Date of Examination:2014-05-08
Date of issue:2015-05-06
Advisor:PD Dr. Halyna Shcherbata
Referee:Prof. Dr. Andreas Wodarz
Referee:Prof. Dr. Jörg Großhans
Persistent Address:
http://dx.doi.org/10.53846/goediss-5054
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Abstract
English
Adult stem cells are found in most adult tissues where they are responsible for replacing cells that are lost due to turnover or injury. They have the unique ability to give rise to differentiated progeny, while at the same time maintaining the stem cell population. In order to preserve tissue homeostasis, these two processes: maintenance versus differentiation have to be tightly regulated. It was shown that surrounding cells form a specific microenvironment, the stem cell niche, that controls the stem cell behavior. The results described in the present thesis show that stem cell progeny differentiation also requires specific interactions with the surrounding cells, the differentiation niche. The D. melanogaster germarium provides an excellent model to study these interactions since adult stem cell maintenance and adult stem cell progeny differentiation can be analyzed in the same well characterized and easy to genetically manipulate organ. We found that components of the ecdysteroid signaling pathway play a role in the germarium. It had been shown previously that ecdysteroids are required for later stages of oogenesis; the present thesis describes how ecdysteroids control the progression through the early stages of germline differentiation. Ecdysone signaling perturbations lead to a germline stem cell progeny differentiation delay. These delayed germline cells display a stem cell-like chromatin state; however, based on the analysis of specific markers, they are not stem cells. Differentiation markers also are not present, indicating that these germline cells are delayed at the pre-cystoblast to cystoblast transition. Interestingly, we found that the ecdysone signaling pathway is acting on the germline cells in a cell non-autonomous way via the somatic germarial cells, a process that requires the spatially restricted cofactors Taiman and Aprupt, activator and inhibitor of ecdysone signaling. Deficit of ecdysone signaling during the development leads to enlarged functional niches, somatic cell differentiation defects and a confused sexual identity. The somatic escort cells fail to appropriately differentiate in the absence of functional ecdysone signaling: shape, division and cell adhesive characteristics are altered; cytoplasmic protrusions, required for interacting with the germline, are not formed and escort cells form a columnar-like epithelium. The cell adhesion proteins Armadillo and DE-Cadherin are found at higher levels in mutant escort cells; which subsequently affects the germline cells responsiveness to Wg signaling. Dampening of Wg signaling in the germline leads to a germline differentiation delay. Furthermore, the miRNA let-7 is modulating the tissue and time specific response to ecdysone via regulating the levels of Abrupt, that is both an inhibitor of ecdysone signaling and a potent regulator of epithelial cell fate. miRNA let-7 is induced by steroids, targets Ab and acts in a feedback loop to ensure the robustness of ecdysone signaling in escort cells in response to changing internal and external conditions such as aging, stress and nutrition.
Keywords: stem cell niche; Drosophila; germarium; miRNA; let-7; ecdysone signaling; germline stem cell; Abrupt; H2Bub1; wingless signaling; histone modifications; differential cell adhesion