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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    • "It has been previously shown that defects in germline encystment by the CySC lineage can block the progression of spermatogonial cells, ultimately leading to the accumulation of early-stage germ cells (Lim and Fuller, 2012; Sarkar et al., 2007). Given that Piwi is required for adult CySC maintenance (Figures 3 and 4), we examined whether the loss of Piwi in the CySC lineage blocks early germ cell differentiation. "
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    ABSTRACT: The Piwi-piRNA pathway is well known for its germline function, yet its somatic role remains elusive. We show here that Piwi is required autonomously not only for germline stem cell (GSC) but also for somatic cyst stem cell (CySC) maintenance in the Drosophila testis. Reducing Piwi activity in the testis caused defects in CySC differentiation. Accompanying this, GSC daughters expanded beyond the vicinity of the hub but failed to differentiate further. Moreover, Piwi deficient in nuclear localization caused similar defects in somatic and germ cell differentiation, which was rescued by somatic Piwi expression. To explore the underlying molecular mechanism, we identified Piwi-bound piRNAs that uniquely map to a gene key for gonadal development, Fasciclin 3, and demonstrate that Piwi regulates its expression in somatic cyst cells. Our work reveals the cell-autonomous function of Piwi in both somatic and germline stem cell types, with somatic function possibly via its epigenetic mechanism. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Preview · Article · Jun 2015 · Cell Reports
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    • "Both GSCs and their first differentiating daughter cells (cystoblasts, CBs) contain a spherical organelle (fusome) that elongates and branches as differentiating CBs form germline cysts. Dividing cysts maintain tight contact with a group of somatic ECs, which are important for their differentiation (Fig. 1A) (Kirilly et al., 2011; Lim and Fuller, 2012; Schulz et al., 2002). "
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    ABSTRACT: Tissue homeostasis is maintained by balancing stem cell self-renewal and differentiation. How surrounding cells support this process has not been entirely resolved. Here we show that the chromatin and telomere-binding factor Without children (Woc) is required for maintaining the association of escort cells (ECs) with germ cells in adult ovaries. This tight association is essential for germline stem cell (GSC) differentiation into cysts. Woc is also required in larval ovaries for the association of intermingled cells (ICs) with primordial germ cells. Reduction in the levels of two other proteins, Stat92E and its target Zfh1, produce phenotypes similar to woc in both larval and adult ovaries, suggesting a molecular connection between these three proteins. Antibody staining and RT-qPCR demonstrate that Zfh1 levels are increased in somatic cells that contact germ cells, and that Woc is required for a Stat92E-mediated upregulation of zfh1 transcription. Our results further demonstrate that overexpression of Zfh1 in ECs can rescue GSC differentiation in woc-deficient ovaries. Thus, Zfh1 is a major Woc target in ECs. Stat signalling in niche cells has been previously shown to maintain GSCs non-autonomously. We now show that Stat92E also promotes GSC differentiation. Our results highlight the Woc-Stat-Zfh1 module as promoting somatic encapsulation of germ cells throughout their development. Each somatic cell type can then provide the germline with the support it requires at that particular stage. Stat is thus a permissive factor, which explains its apparently opposite roles in GSC maintenance and differentiation.
    Preview · Article · Jun 2014 · Development
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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.
    Preview · Article · Apr 2014 · Cell Reports
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