Academic journal article Genetics

Drosophila Glypicans Regulate Follicle Stem Cell Maintenance and Niche Competition

Academic journal article Genetics

Drosophila Glypicans Regulate Follicle Stem Cell Maintenance and Niche Competition

Article excerpt

ALTHOUGH stem cell activity is maintained throughout adult life, individual stem cells often have limited lifespans (Margolis and Spradling 1995). Adult stem cells are replaced regularly to ensure that the niche is always inhabited with functional stem cells (Xie and Spradling 2000; Ryu et al. 2003; Nystul and Spradling 2007). One mechanism of stem cell replacement is competition for niche occupancy between stemcells and their replacement-competent daughters (Nystul and Spradling 2007, 2010; Jin et al. 2008). However, the cellular and molecular bases for stem cell competition for niche occupancy are largely unknown.

Drosophila ovarian follicle stem cells (FSCs) offer an excellent model to study stem cell behavior in an epithelial tissue (Sahai-Hernandez et al. 2012). The Drosophila ovary is composed of 16-20 parallel tubes called ovarioles that contain developing egg chambers arranged in a linear array of progressive developmental stages. During oogenesis, the developing oocyte is interconnected with 15 sister cells, called nurse cells. These developing germ cells are surrounded and supported by a somatic epithelium composed of several different types of somatic follicle cells, which undergo multiple rounds of reorganization to determine the shape of the egg. All follicle cells in each ovariole are derived from two FSCs that reside in separate niches, one on each side of the germarium, which is the most anterior structure of the ovariole (Margolis and Spradling 1995). These FSCs are replaced by a daughter of the remaining stem cell; FSC daughters regularly migrate across the germarium and compete with resident stem cells for niche occupancy (Nystul and Spradling 2007, 2010). Although first identified in Drosophila, this stem cell behavior appears to be a general characteristic of stem cells, including in mammals (Li and Clevers 2010). Since abnormally competitive behaviors of stem cells resemble precancerous events in human epithelia, FSC maintenance and niche competition provide a powerful model to investigate epithelial cancer formation (Nystul and Spradling 2007).

We have previously demonstrated that heparan sulfate proteoglycans (HSPGs) are essential regulators of Drosophila adult stem cells, including germline stem cells (GSC) in the ovary (Hayashi et al. 2009; Dejima et al. 2011) and the testis (Levings et al. 2016), and the intestinal stem cells in the midgut (Takemura and Nakato 2017). HSPGs are a class of carbohydrate-modified proteins composed of heparan sulfate (HS) chains, a long, unbranched glycosaminoglycan, covalently linked to a core protein. They play key roles in numerous biological processes such as growth factor signaling, cell adhesion, and enzymatic catalysis (Esko and Selleck 2002; Kirkpatrick and Selleck 2007). As one of their most important functions, HSPGs serve as coreceptors for secreted signaling ligands. Such HS-dependent factors include fibroblast growth factors, bone morphogenetic proteins, Wnt/Wingless (Wg), Hedgehog (Hh), and Unpaired (Upd), a ligand of the Drosophila Jak/Stat pathway (Li and Kusche-Gullberg 2016; Nakato and Li 2016). HSPGs regulate both signal reception on the cell surface and distribution of the ligand proteins in a tissue (Fujise et al. 2003).

Previous studies of the FSC niche have identified several signaling pathways essential for FSC maintenance. For example, the Hh and Jak/Stat pathways were shown to be key regulators for FSC maintenance (Forbes et al. 1996; Zhang and Kalderon 2000; Hartman et al. 2010; Vied et al. 2012). In addition, Wg signaling plays a critical role for FSC maintenance (Song and Xie 2003; Sahai-Hernandez and Nystul 2013). FSC behavior in response to these signals is dosagedependent, and reception of signaling ligands at FSCs must be tightly regulated (Vied et al. 2012). However, how these pathways are integrated and orchestrated to regulate FSC maintenance and replacement remains to be elucidated. All the ligands of these three pathways, Upd, Hh, and Wg, are known to be HS-dependent and require HSPG coreceptors for proper signaling. …

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