Somatic cell lineage is required for differentiation and not maintenance of germline stem cells in Drosophila testes

Departments of Developmental Biology and Genetics, Stanford University School of Medicine, Stanford, CA 94305.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2012; 109(45). DOI: 10.1073/pnas.1215516109
Source: PubMed


Adult stem cells are believed to be maintained by a specialized microenvironment, the niche, which provides short-range signals that either instruct stem cells to self-renew or inhibit execution of preprogrammed differentiation pathways. In Drosophila testes, somatic cyst stem cells (CySCs) and the apical hub form the niche for neighboring germline stem cells (GSCs), with CySCs as the proposed source of instructive self-renewal signals [Leatherman JL, Dinardo S (2010) Nat Cell Biol 12(8):806-811]. In contrast to this model, we show that early germ cells with GSC characteristics can be maintained over time after ablation of CySCs and their cyst cell progeny. Without CySCs and cyst cells, early germ cells away from the hub failed to initiate differentiation. Our results suggest that CySCs do not have a necessary instructive role in specifying GSC self-renewal and that the differentiated progeny of CySCs provide an environment necessary to trigger GSC differentiation. This work highlights the complex interaction between different stem cell populations in the same niche and how the state of one stem cell population can influence the fate of the other.

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Available from: Margaret T Fuller, Mar 14, 2014
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    • "Staining for Zfh1 indicated that CySCs had returned (Figure 1H). To determine if the new somatic cells were functional, we assayed for the presence of spermatocytes, which cannot form in the absence of cyst cell-derived signals (Lim and Fuller, 2012; Zoller and Schulz, 2012). Although spermatocytes remained immediately after CySC ablation, they were gone from most testes by 1 week of recovery, as expected after a lapse in cyst cell production. "
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    ABSTRACT: Adult stem cells reside in specialized regulatory microenvironments, or niches, where local signals ensure stem cell maintenance. The Drosophila testis contains a well-characterized niche wherein signals from postmitotic hub cells promote maintenance of adjacent germline stem cells and somatic cyst stem cells (CySCs). Hub cells were considered to be terminally differentiated; here, we show that they can give rise to CySCs. Genetic ablation of CySCs triggers hub cells to transiently exit quiescence, delaminate from the hub, and convert into functional CySCs. Ectopic Cyclin D-Cdk4 expression in hub cells is also sufficient to trigger their conversion into CySCs. In both cases, this conversion causes the formation of multiple ectopic niches over time. Therefore, our work provides a model for understanding how oncogenic mutations in quiescent niche cells could promote loss of quiescence, changes in cell fate, and aberrant niche expansion.
    Cell Reports 04/2014; 7(3). DOI:10.1016/j.celrep.2014.03.058 · 8.36 Impact Factor
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    • "In this study the apoptotic gene grim was transiently activated in cyst lineage cells, and this treatment led to ablation of all CySCs and cyst cells in about 80% of the testes. After 1 week, half of the testes had lost all germline cells, while the other half continued to maintain germline cells that failed to differentiate (Lim and Fuller, 2012). In summary, while it is clear that CySCs have the capability to support GSC self-renewal, it is still an open question whether CySCs are absolutely required for GSC maintenance in the setting of the normal niche. "
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    ABSTRACT: Adult stem cell therapies are increasingly prevalent for the treatment of damaged or diseased tissues, but most of the improvements observed to date are attributed to the ability of stem cells to produce paracrine factors that have a trophic effect on existing tissue cells, improving their functional capacity. It is now clear that this ability to produce trophic factors is a normal and necessary function for some stem cell populations. In vivo adult stem cells are thought to self-renew due to local signals from the microenvironment where they live, the niche. Several niches have now been identified which harbor multiple stem cell populations. In three of these niches - the Drosophila testis, the bulge of the mammalian hair follicle, and the mammalian bone marrow - one type of stem cell has been found to produce factors that contribute to the maintenance of a second stem cell population in the shared niche. In this review, I will examine the architecture of these three niches and discuss the molecular signals involved. Together, these examples establish a new paradigm for stem cell behavior, that stem cells can promote the maintenance of other stem cells.
    Frontiers in Genetics 12/2013; 4:257. DOI:10.3389/fgene.2013.00257
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    ABSTRACT: Adult stem cells reside in microenvironments called niches, where they are regulated by both extrinsic cues, such as signaling from neighboring cells, and intrinsic factors, such as chromatin structure. Here we report that in the Drosophila testis niche an H3K27me3-specific histone demethylase encoded by Ubiquitously transcribed tetratricopeptide repeat gene on the X chromosome (dUTX) maintains active transcription of the Suppressor of cytokine signaling at 36E (Socs36E) gene by removing the repressive H3K27me3 modification near its transcription start site. Socs36E encodes an inhibitor of the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway. Whereas much is known about niche-to-stem cell signaling, such as the JAK-STAT signaling that is crucial for stem cell identity and activity, comparatively little is known about signaling from stem cells to the niche. Our results reveal that stem cells send feedback to niche cells to maintain the proper gene expression and architecture of the niche. We found that dUTX acts in cyst stem cells to maintain gene expression in hub cells through activating Socs36E transcription and preventing hyperactivation of JAK-STAT signaling. dUTX also acts in germline stem cells to maintain hub structure through regulating DE-Cadherin levels. Therefore, our findings provide new insights into how an epigenetic factor regulates crosstalk among different cell types within an endogenous stem cell niche, and shed light on the biological functions of a histone demethylase in vivo.
    Development 01/2013; DOI:10.1242/dev.089433 · 6.46 Impact Factor
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