Finding a niche: studies from the Drosophila ovary

Abstract

Specialized microenvironments called niches help maintain stem cells in an undifferentiated and self-renewing state. The existence of niches has long been predicted from mammalian studies, but identifying stem cells in their native environments in vivo has remained a challenge in most vertebrates. Many of the mechanistic insights into how niches regulate stem cell maintenance have been obtained using invertebrate models such as Drosophila. Here, we focus on the Drosophila ovarian germline stem cell niche and review recent studies that have begun to reveal how intricate crosstalk between various signaling pathways regulates stem cell maintenance, how the extracellular matrix modulates the signaling output of the niche and how epigenetic programming influences cell development and function both inside and outside the niche to ensure proper tissue homeostasis. These insights will probably inform the study of mammalian niches and how their malfunction contributes to human disease.

Figure 1

Organization of the developing female gonad and the adult germarium. (a) By the end of larval development, approximately 100 primordial germ cells (PGCs) (red) populate the gonad and associate with cap cell precursor (dark green) and escort cell precursor cells (orange). Terminal filament stacks (light green) begin to form and signal to adjacent somatic cells through the Delta-Notch pathway, inducing them to become cap cells. (b) The differentiation of adult germline cells (red) can be traced based on morphological changes in the fusome (beige), an endoplasmic reticulum-like organelle that appears round in the germline stem cells (GSCs) and becomes increasingly more branched as germline cysts develop [76]. Adult GSCs reside in a niche formed by the terminal filament (light green) and cap cells (dark green). Escort cells (orange) help to guide developing cysts as they pass through the germarium. Eventually a single layer of follicle cells (grey) surrounds the germline cysts and these enveloped cysts bud off the germarium to form an egg chamber.

Figure 2

Signaling within the female germline stem cell niche. (a) Schematic illustrating that Decapentaplegic (Dpp) and Glass bottom boat (Gbb) produced in the anterior of the germarium binds to heterodimeric receptors on the surface of germline stem cells (GSCs). Activation of the receptor results in phosphorylation of Mad (pMad) which then partners with Medea and translocates into the nucleus, where it directly represses the transcription of bag of marbles (bam). This repression is relieved once a GSC daughter leaves the cap cell niche. Smurf, Fused, Brain tumor (Brat) and miR-184 all act to rapidly reduce bone morphogenetic protein (BMP) responsiveness within the cystoblast. Niche signaling is limited to the anterior of the germarium by Lsd1, which represses dpp expression outside the normal niche and by epidermal growth factor (Egf) signaling from the germline, which serves to limit dally expression in the escort cells. EGFR, epidermal growth factor receptor; JAK/STAT, Janus kinase/signal transducer and activator of transcription; pMad, phosphorylated Mothers Against Dpp; Tkv, Thickveins; YB, Female sterile (1) Yb. (b) Components of the extracellular matrix (ECM), including Viking (Vkg; red) and Division abnormally delayed (Dally; green) help to stabilize and limit BMP ligands (blue circles) within the anterior of the germarium. The adherens junction proteins Armadillo (Arm; brown) and Shotgun (Shg; grey) promote cell-cell adhesion between the cap cells (green) and GSCs (dark red).