Germline stem cells: stems of the next generation

Abstract

Germline stem cells (GSCs) sustain gametogenesis during the life of organisms. Recent progress has substantially extended our understanding of GSC behavior, including the mechanisms of stem cell self-renewal, asymmetric stem cell division, stem cell niches, dedifferentiation, and tissue aging. GSCs typically are highly proliferative, owing to organismal requirement to produce large number of differentiated cells. While many somatic stem cells are multipotent, with multiple differentiation pathways, GSCs are unipotent. For these relatively simple characteristics (e.g. constant proliferation and unipotency), GSCs have served as ideal model systems for the study of adult stem cell behavior, leading to many important discoveries. Here, we summarize recent progress in GSC biology, with an emphasis on evolutionarily conserved mechanisms.

Figure 1. Anatomy of GSC niches

(a) Drosophila male GSC niche. GSCs and cyst stem cells (CySCs) are attached to hub cells via adherens junctions (purple crescents). GSCs divide asymmetrically to self-renew and produce a differentiating gonialblast (GB). The GB undergoes four synchronous, transit-amplifying divisions to yield 16 interconnected spermatogonia, through which the fusome (red lines) run. The spectrosome (red sphere) is the spherical version of the fusome found in GSCs. A pair of CySCs encapsulates the GSCs and provides the signals required for GSC identity. Similar to GSCs, CySCs are thought to divide asymmetrically to self-renew and produce cyst cells. Cyst cells exit the cell cycle, a pair of which encapsulates the GB and spermatogonia to promote differentiation. Hub cells secrete the Unpaired (Upd) ligand to activate the JAK-STAT signaling pathway in both GSCs and CySCs to specify their stem cell identity. The Zfh-1 transcription factor acts downstream of the JAK-STAT to specify CySC identity. EGFR signaling ensures the encapsulation of germ cells by cyst cells. The mitotic spindle in GSCs is oriented to ensure the asymmetric stem cell division by positioning a mother centrosome (yellow star) toward the hub and GSC interface. GB and spermatogonia can dedifferentiate to regain GSC identity. (b) Drosophila female GSC niche. GSCs are attached to the cap cells via adherens junctions (purple crescents). GSCs divide asymmetrically to self-renew and produce a differentiating cystoblast (CB). The CB divides four more times to give rise to 16 germ cells interconnected by the fusome, only one of which becomes an oocyte. The remaining 15 cells become nurse cells. Escort stem cells (ESCs), the analog of CySCs, encapsulate the GSC, while their daughters, escort cells, encapsulate the developing germ cells. Cap cells secrete the BMP ligands (dpp and gbb) to repress the key differentiation-promoting factor, Bam, in GSCs to maintain stem cell identity. The JAK-STAT pathway in ESCs contributes to GSC identity. EGFR signaling also ensures the encapsulation of germ cells by cyst cells. The mitotic spindle in GSCs is oriented toward the cap cells via anchoring of one spindle pole to the spectrosome, which localizes consistently to the apical side of GSCs. (c) C. elegans germline stem cell niche. The single distal tip cell (DTC) constitutes the niche for germline stem cells. DTC secretes LAG-2/APX-1 ligands to activate GLP-1/Notch signaling in GSCs. FBF-1 and FBF-2 are the direct downstream targets of GLP-1. No consistent spindle orientation was observed. (d) Mouse spermatogonia stem cell (SSC) niche. Mouse SSCs are found in undifferentiated spermatogonial populations, which are classified as A_s (single cell spermatogonia), A_pr (paired spermatogonia), and A_al (4–16 aligned spermatogonia with interconnected cytoplasm). Spermatogonia are surrounded by Sertoli cells, which are believed to be a major niche component. Leydig cells and blood vessels may also contribute to the SSC niche. Sertoli cells are sealed with tight junctions (purple oval).