GLD-4-Mediated Translational Activation Regulates the Size of the Proliferative Germ Cell Pool in the Adult C. elegans Germ Line
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{"title"=>"GLD-4-Mediated Translational Activation Regulates the Size of the Proliferative Germ Cell Pool in the Adult C. elegans Germ Line", "type"=>"journal", "authors"=>[{"first_name"=>"Sophia", "last_name"=>"Millonigg", "scopus_author_id"=>"55880863100"}, {"first_name"=>"Ryuji", "last_name"=>"Minasaki", "scopus_author_id"=>"16024919500"}, {"first_name"=>"Marco", "last_name"=>"Nousch", "scopus_author_id"=>"16022701500"}, {"first_name"=>"Christian R.", "last_name"=>"Eckmann", "scopus_author_id"=>"35271582500"}], "year"=>2014, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537404", "scopus"=>"2-s2.0-84907588612", "sgr"=>"84907588612", "pui"=>"600082535", "isbn"=>"1553-7390", "pmid"=>"25254367", "doi"=>"10.1371/journal.pgen.1004647"}, "id"=>"832b16ad-0bef-3101-84d7-810201ccee1c", "abstract"=>"To avoid organ dysfunction as a consequence of tissue diminution or tumorous growth, a tight balance between cell proliferation and differentiation is maintained in metazoans. However, cell-intrinsic gene expression mechanisms controlling adult tissue homeostasis remain poorly understood. By focusing on the adult Caenorhabditis elegans reproductive tissue, we show that translational activation of mRNAs is a fundamental mechanism to maintain tissue homeostasis. Our genetic experiments identified the Trf4/5-type cytoplasmic poly(A) polymerase (cytoPAP) GLD-4 and its enzymatic activator GLS-1 to perform a dual role in regulating the size of the proliferative zone. Consistent with a ubiquitous expression of GLD-4 cytoPAP in proliferative germ cells, its genetic activity is required to maintain a robust proliferative adult germ cell pool, presumably by regulating many mRNA targets encoding proliferation-promoting factors. Based on translational reporters and endogenous protein expression analyses, we found that gld-4 activity promotes GLP-1/Notch receptor expression, an essential factor of continued germ cell proliferation. RNA-protein interaction assays documented also a physical association of the GLD-4/GLS-1 cytoPAP complex with glp-1 mRNA, and ribosomal fractionation studies established that GLD-4 cytoPAP activity facilitates translational efficiency of glp-1 mRNA. Moreover, we found that in proliferative cells the differentiation-promoting factor, GLD-2 cytoPAP, is translationally repressed by the stem cell factor and PUF-type RNA-binding protein, FBF. This suggests that cytoPAP-mediated translational activation of proliferation-promoting factors, paired with PUF-mediated translational repression of differentiation factors, forms a translational control circuit that expands the proliferative germ cell pool. Our additional genetic experiments uncovered that the GLD-4/GLS-1 cytoPAP complex promotes also differentiation, forming a redundant translational circuit with GLD-2 cytoPAP and the translational repressor GLD-1 to restrict proliferation. Together with previous findings, our combined data reveals two interconnected translational activation/repression circuitries of broadly conserved RNA regulators that maintain the balance between adult germ cell proliferation and differentiation.", "link"=>"http://www.mendeley.com/research/gld4mediated-translational-activation-regulates-size-proliferative-germ-cell-pool-adult-c-elegans-ge", "reader_count"=>17, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>2, "Student > Master"=>2, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>2, "Student > Master"=>2, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>1, "Sports and Recreations"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1691788"], "description"=>"<p>(A) Diagram of the distal end of an adult germ line (not to scale). Germ cells divide in the proliferative zone (PZ; red circles) and express REC-8 prior to meiotic prophase entry. Germ cells in meiotic prophase (green) express HIM-3 and pSUN-1; leptotene/zygotene (L/Z; half-filled circles) and pachytene (P; squares). In adulthood, a mitosis-to-meiosis boundary (arrowhead) is maintained at a defined distance from the distal tip (asterisk). GCDs, germ cell diameters. (B) Corresponding immunofluorescence micrograph of a distal gonad, illustrating a typical PZ nucleus (red circle) and a crescent-shaped meiotic prophase nucleus (green circle). The mitosis-to-meiosis boundary is apparent from REC-8 and HIM-3 expression. (C,D) Proliferative zone measurements of cytoPAP mutant gonads reveal germ cell (GC) number differences in young adults (L4+24 h). Circle and diamonds to the right side of the table in (C) correspond to the data shown in (D). (E,F) Age-dependent PZ changes are enhanced in <i>gld-4</i> mutants. Dashed line, mitosis-to-meiosis boundary. (G) Quantification of PZ length changes of E and F over time. Error bars, standard deviations.</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183015, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_gld_4_and_gld_2_have_opposing_functions_in_regulating_the_balance_between_proliferation_and_differentiation_/1183015", "title"=>"<i>gld-4</i> and <i>gld-2</i> have opposing functions in regulating the balance between proliferation and differentiation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691795"], "description"=>"<p>(A) Schematic representation of the <i>glp-1</i> 3′UTR reporter transgene. Germline expression of a GFP-Histone 2B-fusion product (GFP::H2B) is driven by the <i>mex-5</i> promoter (<i>mex-5P</i>). GBM, GLD-1-binding motif; HEX, 3′end formation sequence. (B–D, F–I) Micrographs of adult gonads, expressing a GFP::H2B translational <i>glp-1</i> 3′UTR reporter in wild-type, heterozygous (+/−), or homozygous (−/−) mutant backgrounds, reveal <i>gld-4</i>-dependent reporter protein expression. Transgenic animals carry either a wild type (B–D, F–H) or a GBM-mutant (I) <i>glp-1</i> 3′UTR. The penetrance of analyzed germ lines (n) expressing the respective translational reporter is indicated by a color-coded bar (described in A) next to each micrograph. Dashed white lines mark gonads as assessed by DIC microscopy; asterisk, distal tip. Scale bars: 25 µm. (E) Quantification of GFP::H2B protein expression of the <i>glp-1</i> 3′UTRwt translational reporter in given genotypes by α-GFP immunoblotting; tubulin serves as loading control. #, number of animals per lane. (J) Quantification of <i>glp-1</i> 3′UTR reporter mRNA levels by RT-qPCR normalized to <i>rpl-11.1</i> mRNA. Endogenous <i>glp-1</i> mRNA levels were similar among all three genotypes. Error bars are standard error of the mean (SEM). ***, p<0.001; n.s., not significant (Student's t-test).</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183023, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GLD_4_affects_glp_1_3_UTR_GFP_reporter_mRNA_translation_/1183023", "title"=>"GLD-4 affects <i>glp-1</i> 3′UTR GFP reporter mRNA translation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691811"], "description"=>"<p>(A) Median images of extruded gonads stained with α-GLP-1 antibodies in given genetic backgrounds and at two developmental time points. Asterisk, distal tip; arrowhead, mitosis-to-meiosis boundary; empty carat, beginning of pachytene. Scale bars: 10 µm. (B) Quantification of the distal region of immunostained germ lines (n) from A. The α-GLP-1 fluorescent signal was normalized to α-GLH-2 signal. The values of the y-axis represent arbitrary units. Error bars are SEM; p values from Student's t-test. The top scheme indicates the area used for intensity measurements in the distal germ line (black bar). PZ, proliferative zone; L/Z, leptotene/zygotene; other label as in A. (C) Quantification of endogenous <i>glp-1</i> mRNA levels by RT-qPCR normalized to <i>rpl-11.1</i> mRNA. Error bars are SEM. *, p<0.05 (Student's t-test).</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183033, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GLD_4_promotes_endogenous_GLP_1_expression_/1183033", "title"=>"GLD-4 promotes endogenous GLP-1 expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691815"], "description"=>"<p>(A,B) RNA-coimmunoprecipitation experiments (RIPs) of GLD-4 and GLS-1 proteins specifically enrich <i>glp-1</i> mRNA and the positive control <i>gld-1</i> mRNA. <i>eft-3</i> and <i>rpl-11.1</i> mRNA served as negative controls. (A) A representative ethidium bromide-stained agarose gel of semiquantitative RT-PCR products from three independent biological replicates. (B) Quantitative RT-PCR measurements of three additional RIPs. Error bars are SEM. ***, p<0.001; **, p<0.01; n.s., not significant (Student's t-test). (C,D) Translational efficiency of <i>glp-1</i> mRNA depends on <i>gld-4</i> activity. The data are representative of three independent biological experiments. (C) Polysome gradient. Top is to the right; grey peaks represent optical density read of 258 nm; the peaks of the large ribosomal subunit (60S), monosomes (80S), and polysomes are indicated. Relative <i>glp-1</i> mRNA levels are lower in polysome fractions of <i>gld-4</i>(RNAi) as measured by RT-qPCR. (D) Quantification and comparison of <i>glp-1</i> mRNA in pooled polysomal (polys.) and non-polysomal (non-polys.) fractions. Each measurement was normalized to an internal spike-in control (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#s4\" target=\"_blank\">Materials and Methods</a>). Error bars are SEM. *, p<0.05; n.s., not significant (Student's t-test). (E,F) poly(A) tails of <i>glp-1</i> mRNA are reduced upon <i>gld-4</i>(RNAi). (E) Representative PAT assay (n = 2) of the <i>glp-1</i> mRNA material from (C) and the gradient input material. Nucleotide size marker to the left. Lane 7 reflects a 3′UTR with a strongly reduced poly(A) tail (pA) after RNAase H and oligo dT treatment (H/dT). (F) Line scans of PAT assay from (E).</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183037, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_glp_1_mRNA_associates_with_GLD_4_and_is_a_likely_target_of_poly_A_tail_extension_and_translational_activation_/1183037", "title"=>"<i>glp-1</i> mRNA associates with GLD-4 and is a likely target of poly(A) tail extension and translational activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691841"], "description"=>"<p>(A) GLD-4 expression is equal across the distal germ line. GLD-2 intensities increase from low-to-high in a distal-to-proximal manner. Extruded gonads of indicated genotype stained with DAPI, α-GLD-2, α-GLD-4, and α-GLH-2 as a positive tissue penetration control (not shown). Asterisk, distal tip; arrowhead, mitosis-to-meiosis boundary. (B,C) Distal GLD-2 expression is repressed by <i>fbf</i> activity. (B) Example of an <i>fbf</i>(RNAi) immunostained extruded gonad. For the complete RNAi experiment see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#pgen.1004647.s001\" target=\"_blank\">Figure S1</a>. (C) Quantification of the complete <i>fbf</i>(RNAi) experiment. Four different regions of nine germ lines per genotype were analyzed in their median, primarily cytoplasmic area. Error bars are SEM. ***, p<0.001; **, p<0.01; *, p<0.05; bars without indicated p value are statistically not significant (Student's t-test). (D, E) FBF binds specifically to at least one of the five predicted sequence elements in the <i>gld-2</i> 3′UTR. (D) Schematic drawing of the 1094 nt long <i>gld-2</i> 3′UTR. Sequence alignment of FBF-binding element consensus (FBE cons.) sequence <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#pgen.1004647-Lamont1\" target=\"_blank\">[14]</a> and the conserved FBE4 element in three <i>Caenorhabditis</i> species: <i>ce</i>, <i>C. elegans</i>; <i>cb</i>, <i>C. briggsae</i>; <i>cr</i>, <i>C. remanei</i>. pA indicates beginning of the poly(A) tail. (E) Yeast three-hybrid assay. RNA hybrid and Gal4-protein fusions are indicated. FBF-1, FBF-2 and PUF-5 belong to same RNA-binding protein family. Note, the wild-type (wt) and mutant (mut) sequence of FBE4 tested is larger than the given sequences (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#s4\" target=\"_blank\">Materials and Methods</a>). A positive and negative control RNA was included (not shown) and protein expression was confirmed by western blotting (not shown). (F) LAP-tagged FBF-2 associates with endogenous <i>gld-2</i> mRNA in RNA-coimmunoprecipitation experiments (RIPs) directed against the GFP portion of the fusion protein.</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183048, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_GLD_4_and_GLD_2_expression_in_the_proliferative_zone_is_FBF_dependent_/1183048", "title"=>"Differential GLD-4 and GLD-2 expression in the proliferative zone is FBF dependent.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691861"], "description"=>"<p>(A) The current genetic wiring of the core regulatory network that regulates the balance between proliferation and differentiation onset. Two genetic pathways of redundantly acting translational regulators operate downstream of the translational repressor, FBF. A third, yet undefined, pathway has been evoked <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#pgen.1004647-Fox1\" target=\"_blank\">[4]</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#pgen.1004647-Hansen1\" target=\"_blank\">[6]</a>. Note that not all genes are equivalent in the two pathways; only <i>gld-3 nos-3</i> double mutants lack any signs of differentiation <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#pgen.1004647-Eckmann1\" target=\"_blank\">[7]</a>. (B–H) Complete gonads stained with DAPI (left column), and with α-REC-8 and α-HIM-3 (right column) antibodies. Dashed boxes in B and C are close ups of D and E. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#pgen-1004647-t001\" target=\"_blank\">Table 1</a> for the total number of analyzed germ lines. (D–H) Distal region of extruded gonads. Asterisk, distal tip; arrowhead, mitosis-to-meiosis boundary. Scale bars: 50 µm.</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183068, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_gld_4_and_gls_1_promote_onset_of_differentiation_in_parallel_to_gld_2_and_nos_3_/1183068", "title"=>"<i>gld-4</i> and <i>gls-1</i> promote onset of differentiation in parallel to <i>gld-2</i> and <i>nos-3</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691873"], "description"=>"<p>(A–F) Distal region of extruded gonads stained with DAPI, and with α-REC-8, α-HIM-3 (A–E), and α-pSUN-1 (F) antibodies. Asterisk, distal tip; arrowhead, mitosis-to-meiosis boundary. Scale bars: 50 µm. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#pgen-1004647-t001\" target=\"_blank\">Table 1</a> for the total number of analyzed germ lines. (E–F) <i>gld-1 gls-1</i> double mutant germ lines possess a mitosis-to-meiosis boundary, albeit HIM-3 fails to be detected in E. A strong reduction of nucleoplasmic REC-8, the appearance of crescent-shaped nuclei in meiotic prophase (circles in E), and the abundant expression of pSUN-1 (F) reveal onset of differentiation.</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183074, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_gld_4_and_gls_1_promote_onset_of_differentiation_in_parallel_to_gld_2_and_gld_1_/1183074", "title"=>"<i>gld-4</i> and <i>gls-1</i> promote onset of differentiation in parallel to <i>gld-2</i> and <i>gld-1</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691877"], "description"=>"<p>(A–C) DAPI staining of extruded distal gonads from indicated genotypes. Control RNAi and <i>cye-1</i>(RNAi) was conducted by feeding RNAi bacteria to heterozygote mothers and their homozygote progeny was analyzed 24 hrs past L4. Images of the prevailing phenotype and its occurrence out of all germ lines analyzed are given. The <i>gld-3 nos-3</i> tumors served as a positive control for RNAi efficacy. Asterisk, distal tip; arrowhead, mitosis-to-meiosis boundary. Scale bars: 25 µm.</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183078, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.g008"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tumorous_proliferation_of_gld_2_gld_1_gld_4_triple_mutants_depends_on_cye_1_/1183078", "title"=>"Tumorous proliferation of <i>gld-2 gld-1 gld-4</i> triple mutants depends on <i>cye-1</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691882"], "description"=>"<p>(A) Expanded genetic circuitry of primarily translation regulators that fine-tunes the balance between proliferation and differentiation. A light grey box highlights pathway members that regulate differentiation onset. A dark grey box highlights redundant activities that promote GLD-1 expression, primarily when cells commit into meiotic progression (dashed line). See text for details. Note, this simplified circuitry focuses on the RNA regulatory network downstream of GLP-1/Notch and does neither include other known downstream RNA targets nor potential upstream protein regulators. (B) Diagram of translational control examples in proliferative germ cells. Next to <i>glp-1</i> mRNA, GLD-4 may also translationally activate additional mRNAs, encoding proliferation-promoting genes. Additional FBF-regulated mRNAs are known that promote the meiotic program. See text for details. (C) Diagram of translational control examples in differentiating germ cells. Additional GLD-regulated mRNAs are known that promote the proliferative fate. See text for details.</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183081, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.g009"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Translational_regulators_maintain_a_robust_proliferative_zone_in_the_adult_germ_line_/1183081", "title"=>"Translational regulators maintain a robust proliferative zone in the adult germ line.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691888"], "description"=>"1<p>) germ lines that contain germ cells with meiotic character.</p>2<p>) number of germ lines.</p>3<p>) assessed by anti-REC-8, anti-HIM-3, and DAPI staining.</p>4<p>) assessed by anti-REC-8, anti-pSUN-1, and DAPI staining.</p>5<p>) assessed by DAPI staining (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004647#pgen-1004647-g008\" target=\"_blank\">Figure 8</a>).</p><p>Mitosis-to-meiosis decision phenotypes.</p>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183082, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mitosis_to_meiosis_decision_phenotypes_/1183082", "title"=>"Mitosis-to-meiosis decision phenotypes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-09-25 03:57:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1691906", "https://ndownloader.figshare.com/files/1691907", "https://ndownloader.figshare.com/files/1691908"], "description"=>"<div><p>To avoid organ dysfunction as a consequence of tissue diminution or tumorous growth, a tight balance between cell proliferation and differentiation is maintained in metazoans. However, cell-intrinsic gene expression mechanisms controlling adult tissue homeostasis remain poorly understood. By focusing on the adult <i>Caenorhabditis elegans</i> reproductive tissue, we show that translational activation of mRNAs is a fundamental mechanism to maintain tissue homeostasis. Our genetic experiments identified the Trf4/5-type cytoplasmic poly(A) polymerase (cytoPAP) GLD-4 and its enzymatic activator GLS-1 to perform a dual role in regulating the size of the proliferative zone. Consistent with a ubiquitous expression of GLD-4 cytoPAP in proliferative germ cells, its genetic activity is required to maintain a robust proliferative adult germ cell pool, presumably by regulating many mRNA targets encoding proliferation-promoting factors. Based on translational reporters and endogenous protein expression analyses, we found that <i>gld-4</i> activity promotes GLP-1/Notch receptor expression, an essential factor of continued germ cell proliferation. RNA-protein interaction assays documented also a physical association of the GLD-4/GLS-1 cytoPAP complex with <i>glp-1</i> mRNA, and ribosomal fractionation studies established that GLD-4 cytoPAP activity facilitates translational efficiency of <i>glp-1</i> mRNA. Moreover, we found that in proliferative cells the differentiation-promoting factor, GLD-2 cytoPAP, is translationally repressed by the stem cell factor and PUF-type RNA-binding protein, FBF. This suggests that cytoPAP-mediated translational activation of proliferation-promoting factors, paired with PUF-mediated translational repression of differentiation factors, forms a translational control circuit that expands the proliferative germ cell pool. Our additional genetic experiments uncovered that the GLD-4/GLS-1 cytoPAP complex promotes also differentiation, forming a redundant translational circuit with GLD-2 cytoPAP and the translational repressor GLD-1 to restrict proliferation. Together with previous findings, our combined data reveals two interconnected translational activation/repression circuitries of broadly conserved RNA regulators that maintain the balance between adult germ cell proliferation and differentiation.</p></div>", "links"=>[], "tags"=>["translational reporters", "translational activation", "protein expression analyses", "tissue diminution", "proliferative germ cell pool", "adult tissue homeostasis", "elegans Germ Line", "fractionation studies", "organ dysfunction", "cell factor", "RNA regulators", "translational circuit", "proliferative zone", "translational repressor GLD", "mrna", "proliferative germ cells", "tissue homeostasis", "cytoPAP", "differentiation factors", "translational efficiency", "glp", "Cell proliferation", "proliferative cells", "Adult C", "tumorous growth", "translational control circuit", "activator GLS", "fbf", "adult Caenorhabditis elegans", "proliferative adult germ cell pool", "adult germ cell proliferation", "germ cell proliferation"], "article_id"=>1183092, "categories"=>["Biological Sciences"], "users"=>["Sophia Millonigg", "Ryuji Minasaki", "Marco Nousch", "Christian R. Eckmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004647.s001", "https://dx.doi.org/10.1371/journal.pgen.1004647.s002", "https://dx.doi.org/10.1371/journal.pgen.1004647.s003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/GLD_4_Mediated_Translational_Activation_Regulates_the_Size_of_the_Proliferative_Germ_Cell_Pool_in_the_Adult_C_elegans_Germ_Line/1183092", "title"=>"GLD-4-Mediated Translational Activation Regulates the Size of the Proliferative Germ Cell Pool in the Adult <i>C. elegans</i> Germ Line", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-09-25 03:57:35"}

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