Drosophila stem cell niches: a decade of discovery suggests a unified view of stem cell regulation

Abstract

The past decade of research on Drosophila stem cells and niches has provided key insights. Fly stem cells do not occupy a special "state" based on novel "stem cell genes" but resemble transiently arrested tissue progenitors. Moreover, individual stem cells and downstream progenitors are highly dynamic and dispensable, not tissue bulwarks. Niches, rather than fixed cell lineages, ensure tissue health by holding stem cells and repressing cell differentiation inside, but not outside. We review the five best-understood adult Drosophila stem cells and argue that the fundamental biology of stem cells and niches is conserved between Drosophila and mice.

Figure 1.. The ovarian germline stem cell niche: a well understood stem cell model system

(A) A generic niche (dashed line) containing one stem and associated with a niche cell and daughter cell. Two basic niche functions are shown; occupancy (blue) is promoted by stimulating junctions with the niche cell inside, but not outside the niche. Fate regulation (orange) is effected by repressing differentiation genes inside but not outside the niche. (B) The Drosophila ovarian GSC niche contains one GSC and a daughter CB just outside. The niche is generated by terminal filament (Tf), cap, and escort cells. E-cad production is high in the GSC, supporting junctions to the niche. The master switch gene bam is repressed in GSCs by a Jak/STAT to Bmp signaling cascade from the Tf, to cap and escort cells. Bmp reception is turned off in the CB, due to reduced signaling, reduced production of the Bmp co-receptor Dally in response to Egfr signaling, and degradation of the Bmp receptor Tkv. (C) Translational activation of CB differentiation. Differentiating promoting transcripts are repressed in GSC via a Nos/Pum complex and by miRNAs. Bam expression in CB represses E-Cad and Nanos translation, reducing adhesion to the niche and activating differentiation mRNAs.

Figure 2.. Regulation of male germline stem cell niche and de-differentiation

(A) The Drosophila testis niche is shown with one GSC and one CySC, and a daughter GB just outside, associated with a cyst cell. Niche occupancy (blue) is promoted Jak/Stat-stimulated E-Cad expression in the GSC. bam is repressed in GSCs by a Jak/STAT to Bmp signaling cascade from the hub to CySC. Bmp reception is turned off in the GB, due to reduced signaling and dally-like expression, which activates bam and currently unknown differentiation genes (?). (B) The growth of germline cysts downstream from the GSC (red) and its niche is diagrammed for both Drosophila and mouse testis (details are uncertain in the case of mice). Differentiation genes such as bam or ngn-3 turn on in a slow and variable manner in both species (dashed line), prior to the 16-cell stage, which leads to meiosis or commitment to mature (A1) spermatogonial fate. Rarely, (dashed lines) cysts can break down and individual cyst cells can re-enter the niche and become GSCs, providing a stem cell reserve.

Figure 3.. The responsive Drosophila intestinal stem cell lineage

(A) Diagram showing the Drosophila intestinal stem cell (ISC) in its location on the basement membrane, near a recent daughter enteroblast (EB), several mature enterocytes (EC, blue) and a rare enteroendocrine cells (ee, green). (B) The level of the Notch ligand Delta in the ISC acts with the Jak/Stat pathway to specifiy EC v ee fates. (C) Stress, infection, and/or damage to the intestinal epithelium trigger signaling through, Hpo/Wts, Jnk, Jak/Stat, and gfr/Ras/Mapk to modulate the ISC based proliferative response.

Figure 4.. The mouse intestinal stem cell niche

(A) Diagram of a cross section of a mouse intestinal crypt showing stem cellsss (ISC, green) and Paneth cells (blue) (adapted from Snippert et al., 2010). Oriented ISC division generates competition to maximize ISC-Paneth cell contacts between the ISC daughters and neighboring stem cells. One stem cell is forced out of the niche by “neutral competition” and differentiates. (B) Diagram showing similarity between the Drosophila GSC niche (upper drawing) and the mouse ISC niche (lower drawing). Stem cells in both niches are retained by competition for adhesion to niche cells. In the small Drosophila niche, following GSC division the distal daughter usually loses competition for niche contact, exits and differentiations, generating asymmetric daughter cell fates. In the larger mouse niche, one of the recently divided ISC daughters or another adjacent ISC, loses competition for niche contact, exits the niche and differentiates, generating symmetric or asymmetric cell fates. The practical effect of both systems for cell production is similar or identical.