|Home | About | Journals | Submit | Contact Us | Français|
In a recent report in Science, Issigonis et al. (2009) demonstrate that an inhibitor of JAK-STAT signaling controls integrin-mediated niche adhesion in the Drosophila testis, thereby limiting competition between germline and somatic stem cells for niche space.
Stem cells generally reside in specialized niches—spatially constrained microenvironments enriched with signals that ensure self-renewal and prevent differentiation (Spradling et al., 2008). In the Drosophila gonad, niches house germline stem cells (GSCs) and also somatic stem cells (SSCs), which give rise to progeny that provide the differentiating germline with a protective cloak. How does the niche monitor its occupants so that the correct ratio of GSCs to SSCs is maintained? A recent report in Science defines a mechanism in the Drosophila testis in which the two stem cell types are kept in balance by adhesion differences regulated by the signaling pathway that also promotes their identity as stem cells (Issigonis et al., 2009).
In the apical tip of the Drosophila testis, a stem cell niche maintains 8–10 GSCs and approximately twice as many SSCs, called cyst progenitor cells (CPCs) (Davies and Fuller, 2008) (Figure 1A). GSCs divide asymmetrically to produce one daughter that maintains stem cell identity and self-renewal potential and another, the gonialblast, that begins differentiating (Davies and Fuller, 2008) (Figure 1A). Spermatogonia are formed as gonialblasts divide synchronously with incomplete cytokinesis to form 16 germ cell cysts that will terminally differentiate and become mature sperm (Davies and Fuller, 2008). In the niche, CPCs also undergo asymmetric divisions leading to their self-renewal and the production of cyst cells (Davies and Fuller, 2008). Two cyst cells envelop one gonialblast and signal to it via the epidermal growth factor receptor (EGFR) to prevent GSC self-renewal and promote their differentiation into spermatogonia. The ratio of GSCs to CPCs is therefore critical at several steps in spermatogenesis (Davies and Fuller, 2008). Matunis and colleagues (Issigonis et al., 2009) have found a mechanism that operates early in the process to keep these two populations in balance and prevents competition between them for niche space.
Work largely from Drosophila has shown that both signaling and adhesive mechanisms in the niche contribute to the maintenance of stem cell identity. In the Drosophila testis, a cluster of stromal cells called hub cells express the signaling ligand Unpaired (UPD) (Davies and Fuller, 2008). The closely apposed GSCs and CPCs respond by activating the Janus kinases-signal transducer and activator of transcription (JAK-STAT) pathway, and this activation is required for their self renewal (Davies and Fuller, 2008). In addition, both GSCs and CPCs are physically connected to the hub cells via localized expression of β-catenin, E-cadherin, and APC-2, a homolog of the adenomatous polyposis coli tumor suppressor, at adherens junctions (Davies and Fuller, 2008). Issigonis et al. now show that adhesive interactions are also provided by integrins that are regulated by SOCS36E, a target and inhibitor of the JAK/STAT pathway, to prevent competitive displacement of GSCs from the niche (Figure 1B).
SOCS proteins antagonize JAK-STAT signaling by inhibiting JAK kinases and their receptors, providing negative feedback on the pathway. Issigonis et al. expand the role of the JAK-STAT pathway in stem cell maintenance in that this negative feedback loop also regulates the balance between the somatic and germline stem cell pools. They observed that the testis niche of socs36E mutant flies harbors fewer GSCs and a corresponding increase in CPCs. The larger pool of CPCs present in the niche was not due to an increase in their proliferation, but to a local increase in integrin expression within the CPC compartment. Genetic mosaic experiments showed that SOCS36E is required specifically in the CPCs, and in its absence, the region of contact between CPCs and hub cells broadens considerably. Issigonis et al. find that elevating integrin levels specifically in CPCs is both necessary and sufficient for displacement of GSCs from the niche. Thus, SOCS36E modulates the appropriate level of integrin expression, and therefore the adhesion of CPCs to hub cells, in order to prevent CPCs from pushing GSCs out of the niche. In addition, previous work from the Matunis lab reported in Cell Stem Cell demonstrated that overexpression of SOCS36E limits the ability of dedifferentiated germ cells to repopulate the niche (Sheng et al., 2009). The results of both papers therefore suggest that socs36E affects niche occupancy of multiple cell types.
The maintenance of both male and female GSCs (Davies and Fuller, 2008; Spradling et al., 2008) and SSCs (Voog et al., 2008) in Drosophila has thus far been primarily described as cadherin dependent. Differences in E-cadherin levels lead to competition between wild-type GSCs and GSCs mutant for differentiating factors in Drosophila ovarioles (Jin et al., 2008). However, integrins do have roles in stem cell niches; they are essential for hub cell localization in the Drosophila testes and for FSC maintenance in the ovariole (Ellis and Tanentzapf, 2009) and are also implicated in stem cell maintenance in mammalian hematopoietic, neural, and epithelial stem cells (Ellis and Tanentzapf, 2009). Importantly, Issigonis et al. identify modulation of integrin levels as a mechanism for competition between GSCs and CPCs. As a whole, these studies illustrate the importance of adhesive properties in niche occupancy and suggest that somatic and germline stem cells may rely on different proteins to “stick” to the niche.
Although competition has been described between GSCs and dedifferentiated germ cells (Sheng et al., 2009), between FSCs and their daughters in the Drosophila ovariole (Nystul and Spradling, 2007), and between wild-type GSCs and GSCs mutant for differentiation factors in the Drosophila ovariole (Jin et al., 2008), the work of Issigonis et al. demonstrates that two different types of stem cells compete for niche occupation. In stem cell transplantation, host stem cells are often first depleted to make room for the transplanted population, a process that is thought to raise the efficiency of repopulation (Oatley and Brinster, 2008). The unmasking of an inherent ability of different stem cell pools to compete for niche space is important as it suggests that this property could be manipulated therapeutically in the future.
An additional aspect of the Issigonis et al. work is its contribution to our understanding of how the precise ratio of two cyst cells to one gonialblast is maintained during spermatogenesis. It is conceivable that differences in JAK-STAT signaling that affect competition between GSCs and CPCs provide a mechanism to monitor the ratio of GSCs and CPCs and thereby maintain the correct number of each within the niche. Once the cells have left the niche, EGFR signaling from the cyst cells inhibits GSC self-renewal, providing another check on stem cell numbers (Davies and Fuller, 2008). Issigonis et al. note that since SOCS36E inhibits EGFR signaling in other contexts (Callus and Mathey-Prevot, 2002), the intriguing possibility exists that SOCS36E balances the ratio of somatic and germline stem cells through inputs on two different pathways, both in and away from the niche.
Whether SOCS-dependent regulation of integrin is specific to the Drosophila testis remains to be determined, and the JAK-STAT pathway has not yet been identified as a regulator of stem cell niches in mammalian systems. Mammalian systems share some, but not all, signaling pathways with the Drosophila gonadal stem cell niches, and it is feasible that different pathways could converge on similar adhesion proteins. The elucidation of signaling mechanisms that coordinate stem cell populations helps us understand homeostatic relationships between any mixed population of cells, but is especially important for forging new therapeutic inroads in stem cell therapy.