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Cross-Journal Focus Stem Cells Cross-Journal Focus Stem Cells EMBO Molecular Medicine cross-journal focus Stem Cells cross-journal focus Stem Cells EDITORS Thomas Schwarz-Romond Senior Editor [email protected] | T +49 6221 8891 407 Thomas studied Wnt-signal transduction in the lab of Walter Birchmeier at the Max-Delbrueck Center in Berlin and received his PhD from the FU-Berlin in 2003. He continued to investigate this exciting topic as a postdoctoral fellow with Mariann Bienz at the MRC-LMB in Cambridge and joined The EMBO Journal in 2006. Barbara Pauly Senior Editor [email protected] | T +49 6221 8891 109 Barbara joined EMBO Reports in September 2008. She completed her PhD at the University of Munich, focusing on signal transduction in the fresh water polyp Hydra. She worked at the University of California at Berkeley as a post-doctoral researcher, studying the role of the actin cytoskeleton in endocytosis in mammalian cells. Céline Carret Editor [email protected] | T +49 6221 8891 310 Céline Carret completed her PhD at the University of Montpellier, France, characterising host immunodominant antigens to fight babesiosis, a parasitic disease caused by a unicellular EMBO Apicomplexan parasite closely related to the malaria agent Plasmodium. She further developed Molecular her post-doctoral career on malaria working at the Wellcome Trust Sanger Institute in Cambridge, Medicine UK and Instituto de Medicina Molecular in Lisbon, Portugal. Céline joined EMBO Molecular Medicine as a Scientific Editor in March 2011. Maria Polychronidou Editor [email protected] | T +49 6221 8891 410 Maria received her PhD from the University of Heidelberg, where she studied the role of nuclear membrane proteins in development and aging. During her post-doctoral work, she focused on the analysis of tissue-specific regulatory functions of Hox transcription factors using a combination of computational and genome-wide methods. emboj.embopress.org | embor.embopress.org | embomolmed.embopress.org | msb.embopress.org full articles The EMBO Journal Neutral competition of stem cells is skewed by proliferative changes downstream of Hh and Hpo. Amoyel M, Simons BD, Bach EA. DOI: 10.15252/embj.201387500 | Published 04.08.2014 EMBO Reports Review The Hippo signaling pathway in stem cell biology and cancer. Mo JS, Park HW, Guan KL. DOI: 10.15252/embr.201438638 | Published 13.05.2014 Article Heterotrimeric G proteins control stem cell proliferation through CLAVATA signaling in Arabidopsis. Ishida T, Tabata R, Yamada M, Aida M, Mitsumasu K, Fujiwara M, Yamaguchi K, Shigenobu S, Higuchi M, Tsuji H, Shimamoto K, Hasebe M, Fukuda H, Sawa S. DOI: 10.15252/embr.201438660 | Published 26.09.2014 EMBO Molecular Medicine Targeted gene therapy and cell reprogramming in Fanconi anemia. Rio P, Baños R, Lombardo A, Quintana-Bustamante O, Alvarez L, Garate Z, Genovese P, Almarza E, Valeri A, Díez B, Navarro S, Torres Y, Trujillo JP, Murillas R, Segovia JC, Samper E, Surralles J, Gregory PD, Holmes MC, Naldini L, Bueren JA. DOI: 10.15252/emmm.201303374 | Published 23.05.2014 Molecular Systems Biology Intercellular network structure and regulatory motifs in the human hematopoietic system. Qiao W, Wang W, Laurenti E, Turinsky AL, Wodak SJ, Bader GD, Dick JE, Zandstra PW. DOI: 10.15252/msb.20145141 | Published 15.07.2014 For further reading please see inside back cover Article Neutral competition of stem cells is skewed by proliferative changes downstream of Hh and Hpo Marc Amoyel1,*, Benjamin D Simons2,3,4 & Erika A Bach1,5,** Abstract resulting in chance dominance of a clone at the niche. Neutral competition has been established for both vertebrates and inverte- Neutral competition, an emerging feature of stem cell homeosta- brates and in several different tissues (Clayton et al, 2007; Klein sis, posits that individual stem cells can be lost and replaced by et al, 2010; Lopez-Garcia et al, 2010; Snippert et al, 2010; Doupe their neighbors stochastically, resulting in chance dominance of a et al, 2012; de Navascues et al, 2012). However, the fact that loss clone at the niche. A single stem cell with an oncogenic mutation and gain of stem cells occurs opens the possibility of a transformed could bias this process and clonally spread the mutation through- stem cell exploiting this process in its favor and achieving clonal out the stem cell pool. The Drosophila testis provides an ideal dominance. Such behavior theoretically could underlie the observa- system for testing this model. The niche supports two stem cell tion of tumor-initiating cells in certain types of cancer (Reya et al, populations that compete for niche occupancy. Here, we show that 2001) and has recently been reported for mouse intestinal stem cells cyst stem cells (CySCs) conform to the paradigm of neutral compe- (Vermeulen et al, 2013; Snippert et al, 2014). tition and that clonal deregulation of either the Hedgehog (Hh) or The Drosophila testis provides an ideal system for analyzing single Hippo (Hpo) pathway allows a single CySC to colonize the niche. stem cell behavior. The niche (called the hub) supports two stem cell We find that the driving force behind such behavior is accelerated populations, germ line stem cells (GSCs) and somatic cyst stem cells proliferation. Our results demonstrate that a single stem cell (CySCs) (Fig 1A and de Cuevas & Matunis, 2011; Hardy et al, 1979). colonizes its niche through oncogenic mutation by co-opting an GSCs give rise to sperm, while CySCs produce somatic cyst cells, underlying homeostatic process. which ensheath developing germ cells and are required for germ cell differentiation. Each testis niche harbors approximately 9–14 GSCs, Keywords competition; Hedgehog; Hippo; stem cell; testis which divide with oriented mitosis perpendicular to the niche, such Subject Categories Cell Cycle; Development & Differentiation; Stem Cells that one offspring, likely to remain in contact with the niche, self- DOI 10.15252/embj.201387500 | Received 25 November 2013 | Revised 2 July renews while the other, physically displaced from niche signals, 2014 | Accepted 7 July 2014 | Published online 4 August 2014 begins differentiation (Yamashita et al, 2003; Sheng & Matunis, The EMBO Journal (2014) 33: 2295–2313 2011). Serially reconstructed electron micrographs of wild-type testes revealed ~13 somatic cells, presumed to be the CySCs, in contact with See also: ER Morrissey & L Vermeulen (October 2014) the hub in young adults (Hardy et al, 1979). Most current studies rely on immunofluorescence of nuclear factors in presumptive CySCs and their daughters. The best molecular marker of CySCs is Zfh1, which Introduction labels the nucleus of ~44 cells in wild-type testes (Leatherman & Dinardo, 2008; Inaba et al, 2011; Amoyel et al, 2013). This value The ability of a stem cell to continually generate offspring for tissue substantially overestimates the true number of CySCs and includes maintenance depends on its ability to remain and renew at the post-mitotic daughter cells that no longer contact the niche. Finally, niche. A critical consideration is whether stem cells are eternal and there is no evidence for oriented division among CySCs (Cheng et al, always divide invariantly or whether they function as members of 2011), raising the possibility that this population may be subject to an equipotent population, within which a single stem cell could be different regulation than GSCs. Stem cell loss and replacement has lost and replaced stochastically by a neighbor. Recent work has been observed in Drosophila gonads, in both somatic and germ revealed that the latter, termed neutral competition, is an emerging lineages, but its significance remains under debate (Margolis & feature of stem cell homeostasis. This model states that individual Spradling, 1995; Xie & Spradling, 1998, 2000; Zhang & Kalderon, stem cells can be stochastically lost and replaced by their neighbors, 2001; Wallenfang et al, 2006; Nystul & Spradling, 2007). It remains to 1 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA 2 Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK 3 Wellcome Trust-CRUK Gurdon Institute, University of Cambridge, Cambridge, UK 4 Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK 5 The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, New York University School of Medicine, New York, NY, USA *Corresponding author. Tel: +1 212 263 7787; Fax: +1 212 263 8166; E-mail: [email protected] **Corresponding author. Tel: +1 212 263 5963; Fax: +1 212 263 8166; E-mail: [email protected] [The copyright line of this article was changed on 24 October 2014 after original online publication.] ª 2014 The Authors. Published under the terms of the CC BY 4.0 license The EMBO Journal Vol 33 | No 20 | 2014 2295 The EMBO Journal Gain of Hh or Yki cause niche competition Marc Amoyel et al Marc Amoyel et al Gain of Hh or Yki cause niche competition The EMBO Journal A Figure 1. Characterizing the CySC pool. A Left: Schematic of the apical tip of the Drosophila testis. GSCs (red) and CySCs (dark blue) contact the hub (purple). Differentiating progeny move away from the ◂ hub to form germ cysts (red), which are ensheathed by two cyst cells (light blue). Center: Boxed enlargement showing that CySCs form a ring around the hub and contact the hub in between the GSCs. The CySC nucleus (dark blue) resides just ‘behind’ the row of GSCs. A marked CySC (green) will undergo division with possible outcomes depicted at right. Right: In asymmetric renewal (top), the two daughters of the clone give rise to one CySC and one differentiating cyst cell, which ensheaths a gonialblast along with an unmarked cyst cell (light blue). In duplication (middle), both marked daughters remain at the niche as CySCs, displacing an unmarked CySC (blue) in the process. This displaced unmarked cell differentiates into an ensheathing cyst cell.
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