A model of the regulatory network involved in the control of the cell cycle and cell differentiation in the Caenorhabditis elegans vulva

BackgroundThere are recent experimental reports on the cross-regulation between molecules involved in the control of the cell cycle and the differentiation of the vulval precursor cells (VPCs) of Caenorhabditis elegans. Such discoveries provide novel clues on how the molecular mechanisms involved in the cell cycle and cell differentiation processes are coordinated during vulval development. Dynamic computational models are helpful to understand the integrated regulatory mechanisms affecting these cellular processes.ResultsHere we propose a simplified model of the regulatory network that includes sufficient molecules involved in the control of both the cell cycle and cell differentiation in the C. elegans vulva to recover their dynamic behavior. We first infer both the topology and the update rules of the cell cycle module from an expected time series. Next, we use a symbolic algorithmic approach to find which interactions must be included in the regulatory network. Finally, we use a continuous-time version of the update rules for the cell cycle module to validate the cyclic behavior of the network, as well as to rule out the presence of potential artifacts due to the synchronous updating of the discrete model. We analyze the dynamical behavior of the model for the wild type and several mutants, finding that most of the results are consistent with published experimental results.ConclusionsOur model shows that the regulation of Notch signaling by the cell cycle preserves the potential of the VPCs and the three vulval fates to differentiate and de-differentiate, allowing them to remain completely responsive to the concentration of LIN-3 and lateral signal in the extracellular microenvironment.

[1]  A. Yoo,et al.  LIN-12/Notch Activation Leads to MicroRNA-Mediated Down-Regulation of Vav in C. elegans , 2005, Science.

[2]  J. Tyson,et al.  Regulation of the eukaryotic cell cycle: molecular antagonism, hysteresis, and irreversible transitions. , 2001, Journal of theoretical biology.

[3]  H. Horvitz,et al.  The lin-12 locus specifies cell fates in caenorhabditis elegans , 1983, Cell.

[4]  Tim Schedl,et al.  Caenorhabditis elegans lin-45 raf is essential for larval viability, fertility and the induction of vulval cell fates. , 2002, Genetics.

[5]  Mariana Benítez,et al.  Dynamic-module redundancy confers robustness to the gene regulatory network involved in hair patterning of Arabidopsis epidermis , 2010, Biosyst..

[6]  Tibor Vellai,et al.  Transcriptional control of Notch signaling by a HOX and a PBX/EXD protein during vulval development in C. elegans. , 2007, Developmental biology.

[7]  J. Sulston,et al.  Isolation and genetic characterization of cell-lineage mutants of the nematode Caenorhabditis elegans. , 1980, Genetics.

[8]  M. Sundaram,et al.  The love-hate relationship between Ras and Notch. , 2005, Genes & development.

[9]  Iva Greenwald,et al.  Wnt signal from multiple tissues and lin-3/EGF signal from the gonad maintain vulval precursor cell competence in Caenorhabditis elegans , 2007, Proceedings of the National Academy of Sciences.

[10]  K. Kornfeld,et al.  Identification of cis-regulatory elements from the C. elegans Hox gene lin-39 required for embryonic expression and for regulation by the transcription factors LIN-1, LIN-31 and LIN-39. , 2006, Developmental biology.

[11]  Zhongying Zhao,et al.  Boolean genetic network model for the control of C. elegans early embryonic cell cycles , 2013, BioMedical Engineering OnLine.

[12]  Brian Oliver,et al.  Sex-specific DoublesexM expression in subsets of Drosophila somatic gonad cells , 2007, BMC Developmental Biology.

[13]  Paul W Sternberg,et al.  Morphogenesis of the vulva and the vulval-uterine connection. , 2012, WormBook : the online review of C. elegans biology.

[14]  C. Gleissner.  Macrophage Phenotype Modulation by CXCL4 in Atherosclerosis , 2011, Front. Physio..

[15]  Iva Greenwald,et al.  Crosstalk Between the EGFR and LIN-12/Notch Pathways in C. elegans Vulval Development , 2004, Science.

[16]  Robert A. Weinberg,et al.  Functional Inactivation of the Retinoblastoma Protein Requires Sequential Modification by at Least Two Distinct Cyclin-cdk Complexes , 1998, Molecular and Cellular Biology.

[17]  Katherine C. Chen,et al.  Integrative analysis of cell cycle control in budding yeast. , 2004, Molecular biology of the cell.

[18]  J. Sulston,et al.  Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. , 1977, Developmental biology.

[19]  J. Tyson,et al.  Mathematical model of the cell division cycle of fission yeast. , 2001, Chaos.

[20]  Atsushi Yamanaka,et al.  Multiple Skp1-Related Proteins in Caenorhabditis elegans Diverse Patterns of Interaction with Cullins and F-Box Proteins , 2002, Current Biology.

[21]  Amir Pnueli,et al.  Formal Modeling of C. elegans Development: A Scenario-Based Approach , 2003, CMSB.

[22]  Albert Goldbeter,et al.  From quiescence to proliferation: Cdk oscillations drive the mammalian cell cycle , 2012, Front. Physio..

[23]  Paul W. Sternberg,et al.  Predicting Phenotypic Diversity and the Underlying Quantitative Molecular Transitions , 2009, PLoS Comput. Biol..

[24]  Francis Corson,et al.  Geometry, epistasis, and developmental patterning , 2012, Proceedings of the National Academy of Sciences.

[25]  D. Thieffry,et al.  Modular logical modelling of the budding yeast cell cycle. , 2009, Molecular bioSystems.

[26]  Rajat Singhania,et al.  A Hybrid Model of Mammalian Cell Cycle Regulation , 2011, PLoS Comput. Biol..

[27]  M. Park,et al.  Regulation of postembryonic G(1) cell cycle progression in Caenorhabditis elegans by a cyclin D/CDK-like complex. , 1999, Development.

[28]  Edward T Kipreos,et al.  cul-1 Is Required for Cell Cycle Exit in C. elegans and Identifies a Novel Gene Family , 1996, Cell.

[29]  Min Han,et al.  Mutations in cye-1, a Caenorhabditis elegans cyclin E homolog, reveal coordination between cell-cycle control and vulval development. , 2000, Development.

[30]  J. Weiss,et al.  Dynamics of the cell cycle: checkpoints, sizers, and timers. , 2003, Biophysical journal.

[31]  Michele Pagano,et al.  Cell Division, a new open access online forum for and from the cell cycle community , 2006, Cell Division.

[32]  Iva Greenwald,et al.  Notch signaling: genetics and structure. , 2013, WormBook : the online review of C. elegans biology.

[33]  C. Kenyon,et al.  The Hox gene lin-39 is required during C. elegans vulval induction to select the outcome of Ras signaling. , 1998, Development.

[34]  Foong May Yeong,et al.  Anaphase-Promoting Complex in Caenorhabditis elegans , 2004, Molecular and Cellular Biology.

[35]  Paul W. Sternberg,et al.  Opposing Wnt Pathways Orient Cell Polarity during Organogenesis , 2008, Cell.

[36]  Edwin Munro,et al.  Quantitative Variation in Autocrine Signaling and Pathway Crosstalk in the Caenorhabditis Vulval Network , 2011, Current Biology.

[37]  Katherine C. Chen,et al.  Mathematical model of the fission yeast cell cycle with checkpoint controls at the G1/S, G2/M and metaphase/anaphase transitions. , 1998, Biophysical chemistry.

[38]  Adrien Richard,et al.  On Circuit Functionality in Boolean Networks , 2013, Bulletin of mathematical biology.

[39]  James M. Reecy,et al.  Use of Genome Sequence Information for Meat Quality Trait QTL Mining for Causal Genes and Mutations on Pig Chromosome 17 , 2011, Front. Gene..

[40]  Kohei Ogura,et al.  SCF-mediated Cdh1 degradation defines a negative feedback system that coordinates cell-cycle progression. , 2013, Cell reports.

[41]  Paul W. Sternberg,et al.  C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation , 1993, Nature.

[42]  Ning Chen,et al.  The lateral signal for LIN-12/Notch in C. elegans vulval development comprises redundant secreted and transmembrane DSL proteins. , 2004, Developmental cell.

[43]  Arp Schnittger,et al.  A General G1/S-Phase Cell-Cycle Control Module in the Flowering Plant Arabidopsis thaliana , 2012, PLoS genetics.

[44]  Oliver Hobert,et al.  Neurogenesis in the nematode Caenorhabditis elegans. , 2010, WormBook : the online review of C. elegans biology.

[45]  Michael F. Ochs,et al.  Hybrid Modeling of Cell Signaling and Transcriptional Reprogramming and Its Application in C. elegans Development , 2011, Front. Gene..

[46]  Edward T Kipreos,et al.  Ubiquitin-mediated pathways in C. elegans. , 2005, WormBook : the online review of C. elegans biology.

[47]  Paul W Sternberg,et al.  Intercellular coupling amplifies fate segregation during Caenorhabditis elegans vulval development , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[48]  J. Peters,et al.  SCF and APC: the Yin and Yang of cell cycle regulated proteolysis. , 1998, Current opinion in cell biology.

[49]  Richard Roy,et al.  The lin-35/Rb and RNAi pathways cooperate to regulate a key cell cycle transition in C. elegans , 2007, BMC Developmental Biology.

[50]  Edward T Kipreos,et al.  Cyclin E expression during development in Caenorhabditis elegans. , 2003, Developmental biology.

[51]  J. Ferrell,et al.  Modeling the Cell Cycle: Why Do Certain Circuits Oscillate? , 2011, Cell.

[52]  Crisanto Gutierrez,et al.  GEM, a Novel Factor in the Coordination of Cell Division to Cell Fate Decisions in the Arabidopsis Epidermis , 2007, Plant signaling & behavior.

[53]  P. Sternberg,et al.  Multiple functions of let-23, a Caenorhabditis elegans receptor tyrosine kinase gene required for vulval induction. , 1991, Genetics.

[54]  Iva Greenwald,et al.  LIN-14 Inhibition of LIN-12 Contributes to Precision and Timing of C. elegans Vulval Fate Patterning , 2010, Current Biology.

[55]  P. Sternberg,et al.  Competence and commitment of Caenorhabditis elegans vulval precursor cells. , 1999, Developmental biology.

[56]  D. Fay,et al.  The SynMuv genes of Caenorhabditis elegans in vulval development and beyond. , 2007, Developmental biology.

[57]  P. Sternberg,et al.  ARK-1 inhibits EGFR signaling in C. elegans. , 2000, Molecular cell.

[58]  Benjamin Podbilewicz,et al.  LIN-39/Hox triggers cell division and represses EFF-1/fusogen-dependent vulval cell fusion. , 2002, Genes & development.

[59]  Masao Nagasaki,et al.  Simulation-based model checking approach to cell fate specification during Caenorhabditis elegans vulval development by hybrid functional Petri net with extension , 2009, BMC Systems Biology.

[60]  Paul W. Sternberg,et al.  Pattern formation during vulval development in C. elegans , 1986, Cell.

[61]  Paul W. Sternberg,et al.  The gene lin-3 encodes an inductive signal for vulval development in C. elegans , 1992, Nature.

[62]  J. Sulston,et al.  Isolation and genetic characterization of cell-lineage mutants of the nematode Caenorhabditis elegans. , 1980, Genetics.

[63]  S. T. Lamitina,et al.  Dominant mutations in the Caenorhabditis elegans Myt1 ortholog wee-1.3 reveal a novel domain that controls M-phase entry during spermatogenesis. , 2002, Development.

[64]  J. Fisher,et al.  Cell-cycle regulation of NOTCH signaling during C. elegans vulval development , 2012, Molecular systems biology.

[65]  Xiaoyun Sun,et al.  Computational modeling of Caenorhabditis elegans vulval induction , 2007, ISMB/ECCB.

[66]  J. White,et al.  Formation of the vulva in Caenorhabditis elegans: a paradigm for organogenesis. , 1999, Development.

[67]  Simon Melov,et al.  Gene expression changes associated with aging in C. elegans. , 2007, WormBook : the online review of C. elegans biology.

[68]  Andrew D. Chisholm,et al.  Control of cell fates in the central body region of C. elegans by the homeobox gene lin-39 , 1993, Cell.

[69]  Iva Greenwald,et al.  Reciprocal changes in expression of the receptor lin-12 and its ligand lag-2 prior to commitment in a C. elegans cell fate decision , 1994, Cell.

[70]  Y. Shim,et al.  CDC-25.1 controls the rate of germline mitotic cell cycle by counteracting WEE-1.3 and by positively regulating CDK-1 in Caenorhabditis elegans , 2012, Cell cycle.

[71]  Qi Ouyang,et al.  A mathematical model for cell size control in fission yeast. , 2010, Journal of theoretical biology.

[72]  L. Mendoza,et al.  A network model for the specification of vulval precursor cells and cell fusion control in Caenorhabditis elegans , 2013, Front. Genet..

[73]  Thomas R Clandinin,et al.  Different Levels of the C. elegans growth factor LIN-3 promote distinct vulval precursor fates , 1995, Cell.

[74]  David H. Hall,et al.  WormAtlas Hermaphrodite Handbook - Reproductive System - Egg-laying Apparatus , 2004 .

[75]  Phillip D Zamore,et al.  The RNA-Induced Silencing Complex Is a Mg2+-Dependent Endonuclease , 2004, Current Biology.

[76]  Hans A. Kestler,et al.  BoolNet - an R package for generation, reconstruction and analysis of Boolean networks , 2010, Bioinform..

[77]  M. Boxem,et al.  lin-35 Rb and cki-1 Cip/Kip cooperate in developmental regulation of G1 progression in C. elegans. , 2001, Development.

[78]  H. Vodermaier,et al.  APC/C and SCF: Controlling Each Other and the Cell Cycle , 2004, Current Biology.

[79]  David A. Rosenblueth,et al.  Inference of Boolean Networks from Gene Interaction Graphs Using a SAT Solver , 2014, AlCoB.

[80]  R Mako Saito,et al.  The cyclin-dependent kinase inhibitors, cki-1 and cki-2, act in overlapping but distinct pathways to control cell-cycle quiescence during C. elegans development , 2009, Cell cycle.

[81]  A Goldbeter,et al.  A minimal cascade model for the mitotic oscillator involving cyclin and cdc2 kinase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[82]  V. Ambros,et al.  The Cold Shock Domain Protein LIN-28 Controls Developmental Timing in C. elegans and Is Regulated by the lin-4 RNA , 1997, Cell.

[83]  John J. Tyson,et al.  Temporal Organization of the Cell Cycle , 2008, Current Biology.

[84]  J Kimble,et al.  Alterations in cell lineage following laser ablation of cells in the somatic gonad of Caenorhabditis elegans. , 1981, Developmental biology.

[85]  Jonathan Hodgkin,et al.  Introduction to genetics and genomics , 2005 .

[86]  Amir Pnueli,et al.  A scenario-based approach to modeling development: a prototype model of C. elegans vulval fate specification. , 2008, Developmental biology.

[87]  Mike Boxem,et al.  Cyclin-dependent kinases in C. elegans , 2006, Cell Division.

[88]  Sander van den Heuvel,et al.  Cell-cycle control in Caenorhabditis elegans: how the worm moves from G1 to S , 2005, Oncogene.

[89]  J. Tyson,et al.  Modeling the control of DNA replication in fission yeast. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[90]  Adrien Richard,et al.  Boolean Models of Biosurfactants Production in Pseudomonas fluorescens , 2012, PloS one.

[91]  David Harel,et al.  Computational insights into Caenorhabditis elegans vulval development. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[92]  Channing J Der,et al.  Ras effector switching promotes divergent cell fates in C. elegans vulval patterning. , 2011, Developmental cell.

[93]  Iva Greenwald,et al.  LIN-12/Notch trafficking and regulation of DSL ligand activity during vulval induction in Caenorhabditis elegans , 2005, Development.

[94]  Tin Tin Su,et al.  Cell Cycle Regulation , 2007, Fly.

[95]  Thomas A. Henzinger,et al.  Predictive Modeling of Signaling Crosstalk during C. elegans Vulval Development , 2007, PLoS Comput. Biol..

[96]  A. Hajnal,et al.  Notch Inhibition of RAS Signaling Through MAP Kinase Phosphatase LIP-1 During C. elegans Vulval Development , 2001, Science.

[97]  M. Bosenberg,et al.  lag-1, a gene required for lin-12 and glp-1 signaling in Caenorhabditis elegans, is homologous to human CBF1 and Drosophila Su(H). , 1996, Development.

[98]  J. Sulston,et al.  Regulation and cell autonomy during postembryonic development of Caenorhabditis elegans. , 1980, Developmental biology.

[99]  Simon Melov,et al.  Gene expression changes associated with aging in C. elegans. , 2007 .

[100]  G. Seydoux,et al.  Isolation and characterization of mutations causing abnormal eversion of the vulva in Caenorhabditis elegans. , 1993, Developmental biology.

[101]  H. Horvitz,et al.  Identification and characterization of 22 genes that affect the vulval cell lineages of the nematode Caenorhabditis elegans. , 1985, Genetics.

[102]  M. Herman,et al.  Hermaphrodite cell-fate specification. , 2006, WormBook : the online review of C. elegans biology.

[103]  Stuart K. Kim,et al.  Genetic analysis of the Caenorhabditis elegans MAP kinase gene mpk-1. , 1998, Genetics.

[104]  P. Sternberg,et al.  The let-60 locus controls the switch between vulval and nonvulval cell fates in Caenorhabditis elegans. , 1990, Genetics.

[105]  J. Tyson,et al.  The dynamics of cell cycle regulation. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[106]  Stuart K. Kim,et al.  MAP Kinase Signaling Specificity Mediated by the LIN-1 Ets/LIN-31 WH Transcription Factor Complex during C. elegans Vulval Induction , 1998, Cell.

[107]  D. Irons,et al.  Logical analysis of the budding yeast cell cycle. , 2009, Journal of theoretical biology.

[108]  D. M. Eisenmann,et al.  Transcriptional upregulation of the C. elegans Hox gene lin-39 during vulval cell fate specification , 2006, Mechanisms of Development.

[109]  Marie-Anne Félix,et al.  Caenorhabditis elegans vulval cell fate patterning , 2012, Physical biology.

[110]  Michele Pagano,et al.  The F-box protein family , 2000, Genome Biology.

[111]  Luis Mendoza,et al.  Building Qualitative Models of Plant Regulatory Networks with SQUAD , 2012, Front. Plant Sci..

[112]  M. Sundaram,et al.  Canonical RTK-Ras-ERK signaling and related alternative pathways , 2013, WormBook : the online review of C. elegans biology.

[113]  Sander van den Heuvel,et al.  Cell-cycle regulation. , 2005 .

[114]  S. K. Kim,et al.  Protruding vulva mutants identify novel loci and Wnt signaling factors that function during Caenorhabditis elegans vulva development. , 2000, Genetics.

[115]  Stuart K. Kim,et al.  The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development. , 1998, Development.

[116]  Nicolas E. Buchler,et al.  Evolution of networks and sequences in eukaryotic cell cycle control , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[117]  Iva Greenwald,et al.  Endocytosis-mediated downregulation of LIN-12/Notch upon Ras activation in Caenorhabditis elegans , 2002, Nature.

[118]  H. Horvitz,et al.  C. elegans cell-signalling gene sem-5 encodes a protein with SH2 and SH3 domains , 1992, Nature.

[119]  V. Ambros,et al.  Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditis elegans. , 1998, Development.

[120]  D. Sherwood,et al.  Morphogenesis of the Caenorhabditis elegans vulva , 2013, Wiley interdisciplinary reviews. Developmental biology.

[121]  Joseph E Clayton,et al.  Transcriptional control of cell-cycle quiescence during C. elegans development. , 2008, Developmental biology.

[122]  Marie-Anne Félix,et al.  Robustness and flexibility in nematode vulva development. , 2012, Trends in genetics : TIG.

[123]  Q. Ouyang,et al.  The yeast cell-cycle network is robustly designed. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[124]  Richard Roy,et al.  CDC-25.1 stability is regulated by distinct domains to restrict cell division during embryogenesis in C. elegans , 2008, Development.

[125]  L J Dawes,et al.  Interactions between lens epithelial and fiber cells reveal an intrinsic self-assembly mechanism. , 2014, Developmental biology.

[126]  H. Horvitz,et al.  Caenorhabditis elegans ras gene let-60 acts as a switch in the pathway of vulval induction , 1990, Nature.

[127]  Wei Xu,et al.  aph-1 and pen-2 Are Required for Notch Pathway Signaling, γ-Secretase Cleavage of βAPP, and Presenilin Protein Accumulation , 2002 .

[128]  Paul W. Sternberg,et al.  The combined action of two intercellular signaling pathways specifies three cell fates during vulval induction in C. elegans , 1989, Cell.

[129]  Attila Csikász-Nagy,et al.  Analysis of a generic model of eukaryotic cell-cycle regulation. , 2006, Biophysical journal.

[130]  Laura R. Emery,et al.  Protein Phylogenetic Analysis of Ca2+/cation Antiporters and Insights into their Evolution in Plants , 2012, Front. Plant Sci..