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Tim Schedl - One of the best experts on this subject based on the ideXlab platform.

  • Biology of the Caenorhabditis elegans Germline Stem Cell SyStem.
    Genetics, 2019
    Co-Authors: E. Jane Albert Hubbard, Tim Schedl
    Abstract:

    Stem Cell syStems regulate tissue development and maintenance. The Germline Stem Cell syStem is essential for animal reproduction, controlling both the timing and number of progeny through its influence on gamete production. In this review, we first draw general comparisons to Stem Cell syStems in other organisms, and then present our current understanding of the Germline Stem Cell syStem in Caenorhabditis elegans. In contrast to stereotypic somatic development and Cell number stasis of adult somatic Cells in C. elegans, the Germline Stem Cell syStem has a variable division pattern, and the syStem differs between larval development, early adult peak reproduction and age-related decline. We discuss the Cell and developmental biology of the Stem Cell syStem and the Notch regulated genetic network that controls the key decision between the Stem Cell fate and meiotic development, as it occurs under optimal laboratory conditions in adult and larval stages. We then discuss alterations of the Stem Cell syStem in response to environmental perturbations and aging. A recurring distinction is between processes that control Stem Cell fate and those that control Cell cycle regulation. C. elegans is a powerful model for understanding Germline Stem Cells and Stem Cell biology.

  • glp 1 notch lag 1 csl control of the Germline Stem Cell fate is mediated by transcriptional targets lst 1 and sygl 1
    bioRxiv, 2019
    Co-Authors: Tim Schedl, Jian Chen, Ariz Mohammad, Nanette Pazdernik, Huiyan Huang, Beth Bowman, Eric Tycksen
    Abstract:

    Stem Cell syStems are essential for development and maintenance of polarized tissues. InterCellular signaling pathways control Stem Cell syStems, where niche Cells signal Stem Cells to maintain the Stem Cell fate/self renewal and inhibit differentiation. In the C. elegans Germline Stem Cell syStem, GLP-1 Notch signaling specifies the Stem Cell fate. However, the downstream transcriptional targets of GLP-1 signaling that mediate the Stem Cell fate have not been fully enumerated. We employed a genome-wide approach to uncover transcriptional targets of GLP-1 signaling - the intersection of genes identified as directly bound by LAG-1, the C. elegans Notch pathway sequence-specific DNA binding protein, from ChIP-seq experiments, with genes identified as requiring GLP-1 signaling for RNA accumulation, from RNA-seq analysis. lst-1 and sygl-1, genes previously identified as transcriptional targets from a bioinformatic candidate gene approach, were bound by Germline LAG-1 and their expression dependent on glp-1 and Germline lag-1 activity. No additional genes were identified as both bound by LAG-1 and whose mRNA level was dependent on glp-1 and lag-1. Genes were identified as likely secondary effects of GLP-1 signaling with the properties that their glp-1 dependent mRNA accumulation could be explained by a requirement for lst-1 and sygl-1 activity and their lack of LAG-1 binding. Furthermore, glp-1 dependent peak accumulation of FBF-2, which promotes the Stem Cell fate, is explained by a requirement for lst-1 and sygl-1 activity. Finally, we showed that lag-1 is Germline autonomously required for the Stem Cell fate and that elevated LAG-1 accumulation is spatially limited to the Stem Cell region by posttranscriptional regulation that, in part, requires lst-1 and sygl-1. These findings are consistent with the possibility that lst-1 and sygl-1 are the sole Germline GLP-1 signaling mRNA transcriptional targets, which largely or completely mediate the Stem Cell fate.

  • glp 1 notch lag 1 csl control of the Germline Stem Cell fate is mediated by transcriptional targets lst 1 and sygl 1
    bioRxiv, 2019
    Co-Authors: Jian Chen, Ariz Mohammad, Nanette Pazdernik, Huiyan Huang, Beth Bowman, Eric Tycksen, Tim Schedl
    Abstract:

    Abstract Stem Cell syStems are essential for the development and maintenance of polarized tissues. InterCellular signaling pathways control Stem Cell syStems, where niche Cells signal Stem Cells to maintain the Stem Cell fate/self renewal and inhibit differentiation. In the C. elegans Germline, GLP-1 Notch signaling specifies the Stem Cell fate. We undertook a comprehensive genome-wide approach to identify transcriptional targets of GLP-1 signaling. We expected primary response target genes to be evident at the intersection of genes identified as directly bound by LAG-1, the C. elegans Notch pathway sequence-specific DNA binding protein, from ChIP-seq experiments, with genes identified as requiring GLP-1 signaling for RNA accumulation, from RNA-seq analysis. Furthermore, we performed a time-course transcriptomics analysis following auxin inducible degradation of LAG-1 to distinguish between genes whose RNA level was a primary or secondary response of GLP-1 signaling. Surprisingly, only lst-1 and sygl-1, the two known target genes of GLP-1 in the Germline, fulfilled these criteria, indicating that these two genes are the primary response targets of GLP-1 Notch and may be the sole Germline GLP-1 signaling protein-coding transcriptional targets for mediating the Stem Cell fate. In addition, three secondary response genes were identified based on their timing following loss of LAG-1, their lack of a LAG-1 ChIP-seq peak and that their glp-1 dependent mRNA accumulation could be explained by a requirement for lst-1 and sygl-1 activity. Moreover, our analysis also suggests that the function of the primary response genes lst-1 and sygl-1 can account for the glp-1 dependent peak protein accumulation of FBF-2, which promotes the Stem Cell fate and, in part, for the spatial restriction of elevated LAG-1 accumulation to the Stem Cell region. Author Summary Stem Cell syStems are central to tissue development, homeostasis and regeneration, where niche to Stem Cell signaling pathways promote the Stem Cell fate/self-renewal and inhibit differentiation. The evolutionarily conserved GLP-1 Notch signaling pathway in the C. elegans Germline is an experimentally tractable syStem, allowing dissection of control of the Stem Cell fate and inhibition of meiotic development. However, as in many syStems, the primary molecular targets of the signaling pathway in Stem Cells is incompletely known, as are secondary molecular targets, and this knowledge is essential for a deep understanding of Stem Cell syStems. Here we focus on the identification of the primary transcriptional targets of the GLP-1 signaling pathway that promotes the Stem Cell fate, employing unbiased multilevel genomic approaches. We identify only lst-1 and sygl-1, two of a number of previously reported targets, as likely the sole primary mRNA transcriptional targets of GLP-1 signaling that promote the Germline Stem Cell fate. We also identify secondary GLP-1 signaling RNA and protein targets, whose expression shows dependence on lst-1 and sygl-1, where the protein targets reinforce the importance of posttranscriptional regulation in control of the Stem Cell fate.

  • Germline Stem Cell differentiation entails regional control of Cell fate regulator gld 1 in caenorhabditis elegans
    Genetics, 2016
    Co-Authors: John L Brenner, Tim Schedl
    Abstract:

    Germline Stem Cell differentiation in Caenorhabditis elegans is controlled by glp-1 Notch signaling. Cell fate regulator GLD-1 is sufficient to induce meiotic entry and expressed at a high level during meiotic prophase, inhibiting mitotic gene activity. glp-1 signaling and other regulators control GLD-1 levels post-transcriptionally (low in Stem Cells, high in meiotic prophase), but many aspects of GLD-1 regulation are uncharacterized, including the link between glp-1-mediated transcriptional control and post-transcriptional GLD-1 regulation. We established a sensitive assay to quantify GLD-1 levels across an ∼35-Cell diameter field, where distal Germline Stem Cells differentiate proximally into meiotic prophase Cells in the adult C. elegans hermaphrodite, and applied the approach to mutants in known or proposed GLD-1 regulators. In wild-type GLD-1 levels elevated ∼20-fold in a sigmoidal pattern. We found that two direct transcriptional targets of glp-1 signaling, lst-1 and sygl-1, were individually required for repression of GLD-1. We determined that lst-1 and sygl-1 act in the same genetic pathway as known GLD-1 translational repressor fbf-1, while lst-1 also acts in parallel to fbf-1, linking glp-1-mediated transcriptional control and post-transcriptional GLD-1 repression. Additionally, we estimated the position in wild-type gonads where germ Cells irreversibly commit to meiotic development based on GLD-1 levels in worms where glp-1 activity was manipulated to cause an irreversible fate switch. Analysis of known repressors and activators, as well as modeling the sigmoidal accumulation pattern, indicated that regulation of GLD-1 levels is largely regional, which we integrated with the current view of Germline Stem Cell differentiation.

Hwei Jan Hsu - One of the best experts on this subject based on the ideXlab platform.

  • hedgehog signaling establishes precursors for Germline Stem Cell niches by regulating Cell adhesion
    Journal of Cell Biology, 2017
    Co-Authors: Kun-yang Lin, Hwei Jan Hsu, Chunming Lai, Shihhan Kao, Yining Chen, Fu Huang
    Abstract:

    Stem Cells require different types of supporting Cells, or niches, to control Stem Cell maintenance and differentiation. However, little is known about how those niches are formed. We report that in the development of the Drosophila melanogaster ovary, the Hedgehog (Hh) gradient sets differential Cell affinity for somatic gonadal precursors to specify stromal intermingled Cells, which contributes to both Germline Stem Cell maintenance and differentiation niches in the adult. We also report that Traffic Jam (an orthologue of a large Maf transcription factor in mammals) is a novel transcriptional target of Hh signaling to control Cell-Cell adhesion by negative regulation of E-cadherin expression. Our results demonstrate the role of Hh signaling in niche establishment by segregating somatic Cell lineages for differentiation.

  • insulin signals control the competence of the drosophila female Germline Stem Cell niche to respond to notch ligands
    Developmental Biology, 2011
    Co-Authors: Hwei Jan Hsu
    Abstract:

    Adult Stem Cells reside in specialized microenvironments, or niches, that are essential for their function in vivo. Stem Cells are physically attached to the niche, which provides secreted factors that promote their self-renewal and proliferation. Despite intense research on the role of the niche in regulating Stem Cell function, much less is known about how the niche itself is controlled. We previously showed that insulin signals directly stimulate Germline Stem Cell (GSC) division and indirectly promote GSC maintenance via the niche in Drosophila. Insulin-like peptides are required for maintenance of cap Cells (a major component of the niche) via modulation of Notch signaling, and they also control attachment of GSCs to cap Cells and E-cadherin levels at the cap Cell–GSC junction. Here, we further dissect the molecular and Cellular mechanisms underlying these processes. We show that insulin and Notch ligands directly stimulate cap Cells to maintain their numbers and indirectly promote GSC maintenance. We also report that insulin signaling, via phosphoinositide 3-kinase and FOXO, intrinsically controls the competence of cap Cells to respond to Notch ligands and thereby be maintained. Contrary to a previous report, we also find that Notch ligands originated in GSCs are not required either for Notch activation in the GSC niche, or for cap Cell or GSC maintenance. Instead, the niche itself produces ligands that activate Notch signaling within cap Cells, promoting stability of the GSC niche. Finally, insulin signals control cap Cell–GSC attachment independently of their role in Notch signaling. These results are potentially relevant to many syStems in which Notch signaling modulates Stem Cells and demonstrate that complex interactions between local and syStemic signals are required for proper Stem Cell niche function.

  • insulin levels control female Germline Stem Cell maintenance via the niche in drosophila
    Proceedings of the National Academy of Sciences of the United States of America, 2009
    Co-Authors: Hwei Jan Hsu
    Abstract:

    Stem Cell maintenance depends on local signals provided by specialized microenvironments, or niches, in which they reside. The potential role of syStemic factors in Stem Cell maintenance, however, has remained largely unexplored. Here, we show that insulin signaling integrates the effects of diet and age on Germline Stem Cell (GSC) maintenance through the dual regulation of cap Cell number (via Notch signaling) and cap Cell–GSC interaction (via E-cadherin) and that the normal process of GSC and niche Cell loss that occurs with age can be suppressed by increased levels of insulin-like peptides. These results underscore the importance of syStemic factors for the regulation of Stem Cell niches and, thereby, of Stem Cell numbers.

Judith Kimble - One of the best experts on this subject based on the ideXlab platform.

  • non autonomous regulation of Germline Stem Cell proliferation bysomatic mpk 1 mapk activity in c elegans
    bioRxiv, 2020
    Co-Authors: Sarah Robinsonthiewes, Benjamin Dufour, Pierolivier Martel, Xavier Lechasseur, Amani Ange Danielle Brou, Vincent Roy, Yunqing Chen, Judith Kimble, Patrick Narbonne
    Abstract:

    ExtraCellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) is a major positive regulator of Cell proliferation that is often upregulated in cancer. Yet few studies have addressed ERK/MAPK regulation of proliferation within a complete organism. The C. elegans ERK/MAPK ortholog MPK-1 is best known for its control of somatic organogenesis and Germline differentiation, but it also stimulates Germline Stem Cell proliferation. Here we identify tissue-specific MPK-1 isoforms and characterize their distinct roles in Germline function. The Germline-specific MPK-1B isoform promotes Germline differentiation, but has no apparent role in Germline Stem Cell proliferation. By contrast, the soma-specific MPK-1A isoform promotes Germline proliferation non-autonomously. Indeed, MPK-1A functions in the intestine or somatic gonad to promote Germline proliferation, independently of its other known roles. We propose that a non-autonomous role of ERK/MAPK in Stem Cell proliferation may be conserved across species and other tissue types, with major clinical implications for cancer and other diseases.

  • sexual dimorphism of niche architecture and regulation of the caenorhabditis elegans Germline Stem Cell pool
    Molecular Biology of the Cell, 2019
    Co-Authors: Judith Kimble, Sarah L Crittenden, Changhwan Lee, Ipsita Mohanty, Sindhu Battula, Karla M Knobel
    Abstract:

    Stem Cell maintenance by niche signaling is a common theme across phylogeny. In the Caenorhabditis elegans gonad, the broad outlines of Germline Stem Cell (GSC) regulation are the same for both sexes: GLP-1/Notch signaling from the mesenchymal distal tip Cell niche maintains GSCs in the distal gonad of both sexes and does so via two key Stem Cell regulators, SYGL-1 and LST-1. Yet most recent analyses of niche signaling and GSC regulation have focused on XX hermaphrodites, an essentially female sex making sperm in larvae and oocytes in adults. Here we focus on GSC regulation in XO males. Sexual dimorphism of niche architecture, reported previously, suggested that the molecular responses to niche signaling or numbers of GSCs might also be sexually distinct. Remarkably, this is not the case. This work extends our understanding of the sexually dimorphic niche architecture, but also demonstrates that the dimorphic niches drive a similar molecular response and maintain a similar number of GSCs in their Stem Cell pools.

  • a dtc niche plexus surrounds the Germline Stem Cell pool in caenorhabditis elegans
    PLOS ONE, 2014
    Co-Authors: Karla M Knobel, Sarah L Crittenden, Dana T Byrd, Katharyn J Affeldt, Judith Kimble
    Abstract:

    The mesenchymal distal tip Cell (DTC) provides the niche for Caenorhabditis elegans Germline Stem Cells (GSCs). The DTC has a complex Cellular architecture: its Cell body caps the distal gonadal end and contacts germ Cells extensively, but it also includes multiple Cellular processes that extend along the Germline tube and intercalate between germ Cells. Here we use the lag-2 DTC promoter to drive expression of myristoylated GFP, which highlights DTC membranes and permits a more detailed view of DTC architecture. We find that short processes intercalating between germ Cells contact more germ Cells than seen previously. We define this region of extensive niche contact with germ Cells as the DTC plexus. The extent of the DTC plexus corresponds well with the previously determined extent of the GSC pool. Moreover, expression of a differentiation marker increases as germ Cells move out of the plexus. Maintenance of this DTC plexus depends on the presence of undifferentiated germ Cells, suggesting that germ Cell state can influence niche architecture. The roles of this DTC architecture remain an open question. One idea is that the DTC plexus delivers Notch signaling to the cluster of germ Cells comprising the GSC pool; another idea is that the plexus anchors GSCs at the distal end.

Ting Xie - One of the best experts on this subject based on the ideXlab platform.

  • Histone H3K9 trimethylase Eggless controls Germline Stem Cell maintenance and differentiation.
    PLoS genetics, 2011
    Co-Authors: Xiaoxi Wang, Lei Pan, Su Wang, Jian Zhou, William Mcdowell, Jungeun Park, Jeffrey S. Haug, K. Staehling, Hong Tang, Ting Xie
    Abstract:

    Epigenetic regulation plays critical roles in the regulation of Cell proliferation, fate determination, and survival. It has been shown to control self-renewal and lineage differentiation of embryonic Stem Cells. However, epigenetic regulation of adult Stem Cell function remains poorly defined. Drosophila ovarian Germline Stem Cells (GSCs) are a productive adult Stem Cell syStem for revealing regulatory mechanisms controlling self-renewal and differentiation. In this study, we show that Eggless (Egg), a H3K9 methyltransferase in Drosophila, is required in GSCs for controlling self-renewal and in escort Cells for regulating germ Cell differentiation. egg mutant ovaries primarily exhibit germ Cell differentiation defects in young females and gradually lose GSCs with time, indicating that Egg regulates both germ Cell maintenance and differentiation. Marked mutant egg GSCs lack expression of trimethylated H3K9 (H3k9me3) and are rapidly lost from the niche, but their mutant progeny can still differentiate into 16-Cell cysts, indicating that Egg is required intrinsically to control GSC self-renewal but not differentiation. Interestingly, BMP-mediated transcriptional repression of differentiation factor bam in marked egg mutant GSCs remains normal, indicating that Egg is dispensable for BMP signaling in GSCs. Normally, Bam and Bgcn interact with each other to promote GSC differentiation. Interestingly, marked double mutant egg bgcn GSCs are still lost, but their progeny are able to differentiate into 16-Cell cysts though bgcn mutant GSCs normally do not differentiate, indicating that Egg intrinsically controls GSC self-renewal through repressing a Bam/Bgcn-independent pathway. Surprisingly, RNAi-mediated egg knockdown in escort Cells leads to their gradual loss and a germ Cell differentiation defect. The germ Cell differentiation defect is at least in part attributed to an increase in BMP signaling in the germ Cell differentiation niche. Therefore, this study has revealed the essential roles of histone H3K9 trimethylation in controlling Stem Cell maintenance and differentiation through distinct mechanisms.

  • lissencephaly 1 controls Germline Stem Cell self renewal through modulating bone morphogenetic protein signaling and niche adhesion
    Proceedings of the National Academy of Sciences of the United States of America, 2010
    Co-Authors: Shuyi Chen, Satoshi Kaneko, Xiaochu Chen, Ting Xie
    Abstract:

    In the Drosophila ovary, bone morphogenetic protein (BMP) signaling activated by the niche promotes Germline Stem Cell (GSC) self-renewal and proliferation, whereas E-cadherin–mediated Cell adhesion anchors GSCs in the niche for their continuous self-renewal. Here we show that Lissencephaly-1 (Lis1) regulates BMP signaling and E-cadherin–mediated adhesion between GSCs and their niche and thereby controls GSC self-renewal. Lis1 mutant GSCs are lost faster than control GSCs because of differentiation but not because of Cell death, indicating that Lis1 controls GSC self-renewal. The Lis1 mutant GSCs exhibit reduced BMP signaling activity, and Lis1 interacts genetically with the BMP pathway components in the regulation of GSC maintenance. Mechanistically, Lis1 binds directly to and stabilizes the SMAD protein Mothers against decapentaplegic (Mad), facilitates its phosphorylation, and thereby regulates BMP signaling. Finally, the Lis1 mutant GSCs accumulate less E-cadherin in the Stem Cell–niche junction than do their wild-type counterparts. Germline-specific expression of an activated BMP receptor thickveins (Tkv) or E-cadherin can partially rescue the loss phenotype of Lis1 mutant GSCs. Therefore, this study has revealed a role of Lis1 in the control of Drosophila ovarian GSC self-renewal, at least partly by regulating niche signal transduction and niche adhesion. It has been known that Lis1 controls neural precursor/Stem Cell proliferation in the developing mammalian brain; this study further suggests that Lis1, which is widely expressed in adult mammalian tissues, could regulate adult tissue Stem Cells through modulating niche signaling and adhesion.

  • notch signaling controls Germline Stem Cell niche formation in the drosophila ovary
    Development, 2007
    Co-Authors: Xiaoqing Song, Daniel Kirilly, Gerald B Call, Ting Xie
    Abstract:

    Stem Cells, which can self-renew and generate differentiated Cells, have been shown to be controlled by surrounding microenvironments or niches in several adult tissues. However, it remains largely unknown what constitutes a functional niche and how niche formation is controlled. In the Drosophila ovary, Germline Stem Cells (GSCs), which are adjacent to cap Cells and two other Cell types, have been shown to be maintained in the niche. In this study, we show that Notch signaling controls formation and maintenance of the GSC niche and that cap Cells help determine the niche size in the Drosophila ovary. Expanded Notch activation causes the formation of more cap Cells and bigger niches, which support more GSCs, whereas compromising Notch signaling during niche formation decreases the cap Cell number and niche size and consequently the GSC number. Furthermore, the niches located away from their normal location can still sufficiently sustain GSC self-renewal by maintaining high local BMP signaling and repressing bam as in normal GSCs. Finally, loss of Notch function in adults results in rapid loss of the GSC niche, including cap Cells and thus GSCs. Our results indicate that Notch signaling is important for formation and maintenance of the GSC niche, and that cap Cells help determine niche size and function.

  • molecular mechanisms of Germline Stem Cell regulation
    Annual Review of Genetics, 2005
    Co-Authors: Marco D Wong, Zhigang Jin, Ting Xie
    Abstract:

    AbstractGermline Stem Cells (GSCs), which can self-renew and generate differentiated progeny, are unique Stem Cells in that they are solely dedicated to reproduction and transmit genetic information from generation to generation. Through the use of genetic techniques in Drosophila, Caenorhabditis elegans, and mouse, exciting progress has been made in understanding molecular mechanisms underlying interactions between Stem Cells and niches. The knowledge gained from studying GSCs has provided an intellectual framework for defining niches and molecular regulatory mechanisms for other adult Stem Cells. In this review, we summarize recent progress and discuss conserved mechanisms underlying GSC self-renewal and differentiation by comparing three GSC syStems. Because GSCs and other adult Stem Cells share “Stemness,” we hope this review will help define fundamental principles of Stem Cell regulation and provide further guidance for future studies of other adult Stem Cells.

Stephen Dinardo - One of the best experts on this subject based on the ideXlab platform.

  • dynamics of the male Germline Stem Cell population during aging of drosophila melanogaster
    Aging Cell, 2006
    Co-Authors: Matthew R Wallenfang, Renuka R Nayak, Stephen Dinardo
    Abstract:

    Summary Drosophila melanogaster has emerged as an important model syStem for the study of both Stem Cell biology and aging. Much is known about how molecular signals from the somatic niche regulate adult Stem Cells in the Germline, and a variety of environmental factors as well as single point mutations have been shown to affect lifespan. Relatively little is known, however, about how aging affects specific populations of Cells, particularly adult Stem Cells that may be susceptible to aging-related damage. Here we show that male Germline Stem Cells (GSCs) are lost from the Stem Cell niche during aging, but are efficiently replaced to maintain overall Stem Cell number. We also find that the division rate of GSCs slows significantly during aging, and that this slowing correlates with a reduction in the number of somatic hub Cells that contribute to the Stem Cell niche. Interestingly, slowing of Stem Cell division rate was not observed in long-lived methuselah mutant flies. We finally investigated whether two mechanisms that are thought to be used in other adult Stem Cell types to minimize the effects of aging were operative in this syStem. First, in many adult tissues Stem Cells exhibit markedly fewer Cell cycles relative to transit-amplifying Cells, presumably protecting the Stem Cell pool from replication-associated damage. Second, at any given time not all Stem Cells actively cycle, leading to ‘clonal succession’ from the reserve pool of initially quiescent Stem Cells. We find that neither of these mechanisms is used in Drosophila male GSCs.

  • somatic control over the Germline Stem Cell lineage during drosophila spermatogenesis
    Nature, 2000
    Co-Authors: John Tran, Tamara J Brenner, Stephen Dinardo
    Abstract:

    Stem Cells divide both to produce new Stem Cells and to generate daughter Cells that can differentiate1. The underlying mechanisms are not well understood, but conceptually are of two kinds2. Intrinsic mechanisms may control the unequal partitioning of determinants leading to asymmetric Cell divisions that yield one Stem Cell and one differentiated daughter Cell. Alternatively, extrinsic mechanisms, involving stromal Cell signals, could cause daughter Cells that remain in their proper niche to stay Stem Cells, whereas daughter Cells that leave this niche differentiate. Here we use Drosophila spermatogenesis as a model Stem Cell syStem3 to show that there are excess Stem Cells and gonialblasts in testes that are deficient for Raf activity. In addition, the Germline Stem Cell population remains active for a longer fraction of lifespan than in wild type. Finally, raf is required in somatic Cells that surround germ Cells. We conclude that a Cell-extrinsic mechanism regulates Germline Stem Cell behaviour.

  • bag of marbles and benign gonial Cell neoplasm act in the Germline to restrict proliferation during drosophila spermatogenesis
    Development, 1997
    Co-Authors: Pierre Gonczy, Erika Matunis, Stephen Dinardo
    Abstract:

    Stem Cells divide asymmetrically, regenerating a parental Stem Cell and giving rise to a daughter Cell with a distinct fate. In many Stem Cell lineages, this daughter Cell undergoes several amplificatory mitoses, thus generating more Cells that embark on the differentiation program specific for the given lineage. Spermatogenesis in Drosophila is a model syStem to identify molecules regulating Stem Cell lineages. Mutations at two previously identified loci, bag-of-marbles (bam) and benign gonial Cell neoplasm (bgcn), prevent progression through spermatogenesis and oogenesis, resulting in the overproliferation of undifferentiated germ Cells. Here we investigate how bam and bgcn regulate the male Germline Stem Cell lineage. By generating FLP-mediated clones, we demonstrate that both bam and bgcn act autonomously in the Germline to restrict proliferation during spermatogenesis. By using enhancer trap lines, we find that the overproliferating germ Cells express markers specific to amplifying germ Cells, while at the same time retaining the expression of some markers of Stem Cell and primary spermatogonial Cell fate. However, we find that germ Cells accumulating in bam or bgcn mutant testes most resemble amplifying germ Cells, because they undergo incomplete cytokinesis and progress through the Cell cycle in synchrony within a cyst, which are two characteristics of amplifying germ Cells, but not of Stem Cells. Taken together, our results suggest that bam and bgcn regulate progression through the male Germline Stem Cell lineage by Cell-intrinsically restricting the proliferation of amplifying germ Cells.