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D. melanogaster

Drosophila mesoderm specification

Summary: 

This logical model encompasses 48 components and 82 regulatory interactions controlling mesoderm specification during Drosophila development, thereby integrating all major genetic processes underlying the formation of four mesodermal tissues. The model is based on in vivo genetic data, partly confirmed by functional genomic data.

Model simulations qualitatively recapitulate the expression of the main lineage markers of each mesodermal derivative, from developmental stage 8 to 10, for the wild type case, as well as for over twenty reported mutant genotypes.

This model has been used to systematically predict the effects of over 300 loss- and gain-off unction mutations, and combinations thereof. By generating specific mutant combinations, several novel predictions experimentally could be validated, demonstrating the robustness of model.

Curation
Submitter: 
Denis Thieffry

Drosophila eggshell patterning

Summary: 

The Drosophila eggshell constitutes a remarkable system for the study of epithelial patterning, both experimentally and through computational modeling. Dorsal eggshell appendages arise from specific regions in the anterior follicular epithelium that covers the oocyte: two groups of cells expressing broad (roof cells) bordered by rhomboid expressing cells (floor cells). Despite the large number of genes known to participate in defining these domains and the important modeling efforts put into this developmental system, key patterning events still lack a proper mechanistic understanding and/or genetic basis, and the literature appears to conflict on some crucial points.
We tackle these issues with an original, discrete framework that considers single-cell models that are integrated to construct epithelial models. We first build a phenomenological model that reproduces wild type follicular epithelial patterns, confirming EGF and BMP signaling input as sufficient to establish the major features of this patterning system within the anterior domain. Importantly, this simple model predicts an instructive juxtacrine signal linking the roof and floor domains. To explore this prediction, we define a mechanistic model that integrates the combined effects of cellular genetic networks, cell communication and network adjustment through developmental events. Moreover, we focus on the anterior competence region, and postulate that early BMP signaling participates with early EGF signaling in its specification. This model accurately simulates wild type pattern formation and is able to reproduce, with unprecedented level of precision and completeness, various published gain-of-function and loss-of-function experiments, including perturbations of the BMP pathway previously seen as conflicting results. The result is a coherent model built upon rules that may be generalized to other epithelia and developmental systems.

Here, we provide the two single cell models (phenomenological and mechanistic).

The Python prototype to simulate epithelial models together with all model files are given on a different page.

The multicellular model versions are also available at the EpiLog model repository.

Curation
Submitter: 
C. Chaouiya

Drosophila VEGF Signalling pathway

Summary: 

VEGF (also called PDGF or PVF) pathway participates in different developmental processes, including border cell migration, hemocyte migration and survival, thorax closure during metamorphosis, the rotation and dorsal closure of the male terminalia. and embryonic salivary gland tissue migration. The ability of PVR to activate the MAP-kinase pathway is important for control of cell growth and differentiation in other tissues. Three genes in the Drosophila genome code for PVR ligands: PVF1, PVF2, and PVF3. Binding of one of the ligands (PVF1, 2 or 3) to the receptor PVR triggers the canonical DRK/SOS/RAS/RAF/DSOR1/RL pathway ([1];[2]; [3]; [4]; [5]). DOF is needed to assemble the PVR receptor and allow it to auto-phosphorylate, likely as an adaptor that links the receptor to RAS pathway. DOF is a cytoplasmic protein which is expressed ubiquitously only in cells that express the FGF receptors. It contains an ankyrin repeat, a coiled-coil structure and many tyrosines within environments that suggest that if phosphorylated they act as binding sites for the SH2 domains of proteins such as DRK or CSW ([6]). The SH2-domain-containing protein DRK recruits the guanine nucleotide exchange factor, Son of sevenless (SOS), to catalyze the exchange of GDP bound to RAS for GTP, thereby activating RAS with the help of activated KSR. RAS promotes the activation of RAF, leading to the activation of DSOR1, and ultimately to that of the MAP kinase Rolled (RL ). Rolled can activate transcription, both through inactivation of transcriptional co-repressors such as AOP, as well as through the activation of transcription factors such as the ETS-domain- containing protein Pointed (PNT) ([7]; [8]). The activation of PNT is a major output of the pathway. It is either phosphorylated by MAP kinase to produce an active transcriptional activator (PointedP2), or transcriptionally induced by MAP kinase to produce a constitutive transcriptional activator (PointedP1). Sprouty (STY) acts downstream of the receptor, but upstream of RAS1 and RAF, by recruiting GAP1 and blocking the ability of DRK to bind to its positive effector. We have considered three typical initial states corresponding to i. ligands binding in wild-type signalling enabling situation (VEGF_signalling), ii. ligand binding in the presence of the inhibitor Sprouty (Sprouty_inhibition), iii. absence of ligand (No_signalling).


References

Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila Toll Signalling pathway

Summary: 

Toll was initially discovered as an essential component of the pathway that establishes the dorsal, ventral axis of the early Drosophila embryo. If any component in that genetic pathway is missing, no ventral or lateral cell types develop and the resulting embryos lack all mesoderm and the entire nervous system ([1]). Fungal and Gram-positive bacterial infections in Drosophila also stimulate the Toll pathway. Activation of Toll leads to recruitment of three cytoplasmic proteins, which are MYD88, Tube and Pelle, to form the signalling complex underneath the cell membrane ([2]). Subsequently, through interactions via death domains, assembly of the signalling complex containing MYD88, Tube and Pelle occurs ([2]; [3]). From this complex, signalling proceeds through the phosphorylation and degradation of the Drosophila IkB factor Cactus. In non signaling conditions, Cactus is bound to Dorsal or Dorsal-related immunity factor (DIF), inhibiting their activity and nuclear localization. Pelle is the only kinase reported for Cactus phosphorylation. After phosphorylation, nuclear translocation of Dorsal/DIF leads to activation of transcription of several sets of target genes. ([3]; [4]). To reproduce pathway signalling dynamics, we define two initial states corresponding to no signalling conditions (no ligand binding) and to signalling conditions (binding of SPZ to the receptor Toll).


References

  1. Anderson KV.  2000.  Toll signaling pathways in the innate immune response.. Current opinion in immunology. 12(1):13-9.
  2. Sun H, Towb P, Chiem DN, Foster BA, Wasserman SA.  2004.  Regulated assembly of the Toll signaling complex drives Drosophila dorsoventral patterning.. The EMBO journal. 23(1):100-10.
  3. Tanji T, Ip TY.  2005.  Regulators of the Toll and Imd pathways in the Drosophila innate immune response.. Trends in immunology. 26(4):193-8.
  4. Valanne S, Wang J-H, Rämet M.  2011.  The Drosophila Toll signaling pathway.. Journal of immunology (Baltimore, Md. : 1950). 186(2):649-56.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila Hh Signalling pathway

Summary: 

Processing of HH ligand The precursor of HH is auto-catalytically cleaved to produce an N-terminal (HH-N) and a C- terminal (HH-C) fragments ([1]; [2]). A cholesterol moiety is covalently attached to the last amino acid of HH-N to create HH-Np, that is responsible for the biological activities of HH proteins ([1]; [2]; [3]). The N-terminal region of HH-Np is further modified by addition of palmitate that is essential for its signalling activity ([4]; [5]; [6]; [7]; [8]; [9]). We model these aspects by an AND rule (combining inputs from DLP, IHOG, Rasp, DISP, SHF, Lipophorin, BOI and DALLY) attached to the component representing the secreted HH molecule, denoted Hh in our model. HH Signalling Two integral membrane proteins are involved in HH signal reception: Patched and Smoothened. HH binding to its receptor Patched (PTC) relieves PTC-mediated repression of Smoothened (SMO), a serpentine-like membrane protein required for HH signalling ([10]; [11]). This allows SMO stabilisation, activation, and phosphorylation by Shaggy (SGG), and downstream signalling through the formation of a protein complex including the serine threonine kinase Fused (FU), the kinesin-like protein Costa (COS), and the protein Suppressor of Fused (SU(FU)), ultimately controlling the post-translational processing of the protein Cubitus interruptus (CI) ([12]). In the absence of HH, COS binds CI directly and sequesters it in the cytoplasm with the help of SUFU. The recruitment of different kinases (Casein kinase 1 alpha, Shaggy, Protein kinase A) then leads to the phosphorylation of CI and to its proteolysis by SLMB. The resulting truncated protein (CI_rep) is released and enters the nucleus, where it has a transcriptional repressing activity. Recent evidence further indicates that SMO is inhibited by TOW, which tentatively mediates the effect of PTC on SMO ([13]; [14]). Following SMO activation, the transcription factor CI is phosphorylated and translocated into the nucleus in its entire form, which plays a transcriptional activatory role (CI_act). In the model, a cascade of inhibitions, from HH on PTC, and from PTC on SMO, implements the indirect positive action of HH on SMO. A protein complex including CI, COS, and FU, phosphorylates and thereby inhibits SU(FU), ultimately favouring the CI activatory form and its translocation into the nucleus. We model the roles of the kinases (SGG, PKA, and CK1a), COS and SU(FU) (both needed to recruit the kinases) in the processing of CI in terms of inhibitory interactions on CI_act and activatory interactions on CI_rep ([15]; [16]). Complexes are represented implicitly (they are formed as soon as the components are synthesised or activated), while logical rules define component activity requirements to form CI_act versus CI_rep forms. To explore the dynamic of the pathway, we define two initial states to simulate the presence and the absence of signalling. On one hand, the non binding of HH (level expression 0) triggers a series of signalling cascades that lead to the activation of several kinases (for example SGG, PKA, CK1a, ...) at level of expression 1, which will permit the formation of CI repressor (expressed at level 1), which in turn will inhibit the targets. On the other hand, the presence of HH (level of expression 1) leads to a stable state corresponding to the signalling conditions leading to the formation of CI activator that will activate the targets node (level of expression 1).


References

  1. Lee JJ, Ekker SC, von Kessler DP, Porter JA, Sun BI, Beachy PA.  1994.  Autoproteolysis in hedgehog protein biogenesis.. Science (New York, N.Y.). 266(5190):1528-37.
  2. Porter JA, Young KE, Beachy PA.  1996.  Cholesterol modification of hedgehog signaling proteins in animal development.. Science (New York, N.Y.). 274(5285):255-9.
  3. Ingham PW, McMahon AP.  2001.  Hedgehog signaling in animal development: paradigms and principles.. Genes & development. 15(23):3059-87.
  4. Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K et al..  1998.  Identification of a palmitic acid-modified form of human Sonic hedgehog.. The Journal of biological chemistry. 273(22):14037-45.
  5. Wang G, Amanai K, Wang B, Jiang J.  2000.  Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus.. Genes & development. 14(22):2893-905.
  6. Amanai K, Jiang J.  2001.  Distinct roles of Central missing and Dispatched in sending the Hedgehog signal.. Development (Cambridge, England). 128(24):5119-27.
  7. Chamoun Z, Mann RK, Nellen D, von Kessler DP, Bellotto M, Beachy PA, Basler K.  2001.  Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal.. Science (New York, N.Y.). 293(5537):2080-4.
  8. Lee JD, Treisman JE.  2001.  The role of Wingless signaling in establishing the anteroposterior and dorsoventral axes of the eye disc.. Development (Cambridge, England). 128(9):1519-29.
  9. Micchelli CA, The I, Selva E, Mogila V, Perrimon N.  2002.  Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling.. Development (Cambridge, England). 129(4):843-51.
  10. Alcedo J, Ayzenzon M, Von Ohlen T, Noll M, Hooper JE.  1996.  The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal.. Cell. 86(2):221-32.
  11. Chen Y, Struhl G.  1996.  Dual roles for patched in sequestering and transducing Hedgehog.. Cell. 87(3):553-63.
  12. Lum L, Yao S, Mozer B, Rovescalli A, Von Kessler D, Nirenberg M, Beachy PA.  2003.  Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells.. Science (New York, N.Y.). 299(5615):2039-45.
  13. Ayers KL, Rodriguez R, Gallet A, Ruel L, Thérond P.  2009.  Tow (Target of Wingless), a novel repressor of the Hedgehog pathway in Drosophila.. Developmental biology. 329(2):280-93.
  14. Ayers KL, Thérond PP.  2010.  Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling.. Trends in cell biology. 20(5):287-98.
  15. Aikin RA, Ayers KL, Thérond PP.  2008.  The role of kinases in the Hedgehog signalling pathway.. EMBO reports. 9(4):330-6.
  16. Wilson CW, Chuang P-T.  2006.  New "hogs" in Hedgehog transport and signal reception.. Cell. 125(3):435-8.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila SPATZLE Processing pathway

Summary: 

During DV patterning, a regulatory cascades composed by three dorsal group genes gastrulation-defective, snake and easter, encoding serine proteases, lead to the cleavage of Spatzle (SPZ), that in turn activates the Toll-dorsal signaling pathway ([1]; [2]). Spatzle presumably forms a gradient in the perivitelline fluid. Toll signaling is ultimately responsible for the formation of the embryonic dorsal nuclear gradient. In the nucleus, dorsal controls the expression of zygotic genes in a concentration-dependent manner and this process results in the patterning of the dorsal–ventral embryonic axis. twist is one of the earliest target genes controlled by the highest concentration of dorsal in the mesodermal cells. It is a transcriptional activator that cooperates with dorsal in activating snail in the mesoderm. Dorsal and Twist also cooperate to activate the neurogenic gene, sim (single minded), expressed in the neurectoderm and repressed by Snail in the mesoderm. Natural or experimentally induced infections by fungi or bacteria elicit a specific response in both adult flies and larvae. The proteoglycans of Gram-positive and Gram-negative bacteria are sensed by distinct pattern recognition proteins called PGRPs (peptidoglycan recognition proteins ([3]). Different PRGPs cooperate to activate the Toll pathway. The activation of PGRP-SA by Gram- positive bacteria leads to Spatzle cleavage ([4]). Fungal infection also leads to the cleavage of Spatzle, but the proteolytic cascade in this case involves the circulating serine protease Persephone and its serine protease inhibitor, Necrotic ([5]; [6]; [7]). Circulating PGRP-SA receptor activates the Toll pathway upon detection of Lysine-type PGN which is a major component of the cell wall of many Gram-positive bacterial strains. GNBP1 (Gram-Negative Binding Protein 1) associates with PGRP-SA and this complex activates a downstream proteolytic cascade that leads to the cleavage of Spatzle, which then activates the Toll transmembrane receptor. In addition, four other serine proteases, namely Spirit, Spheroide, and Sphinx1 and 2, were identified in response to both fungi and Gram-positive bacteria infections. Thus, PGRP-SA and GNBP1 define a Gram-positive-specific branch of Toll receptor activation. PGRP-SD also belongs to this branch and is required for the detection of other Gram-positive and negative bacterial strains. In short, the maturation of SPZ activates Toll in both early embryo and immune response and is controlled by different sets of proteases ([8]; [9]). To reproduce biological data during SPZ processing, we define four initial states corresponding the biological process involved. All these initial state lead to the formation of the active form of SPZ.


References

  1. Morisato D, Anderson KV.  1994.  The spätzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo.. Cell. 76(4):677-88.
  2. Weber ANR, Tauszig-Delamasure S, Hoffmann JA, Lelièvre E, Gascan H, Ray KP, Morse MA, Imler J-L, Gay NJ.  2003.  Binding of the Drosophila cytokine Spätzle to Toll is direct and establishes signaling.. Nature immunology. 4(8):794-800.
  3. Royet J.  2004.  Drosophila melanogaster innate immunity: an emerging role for peptidoglycan recognition proteins in bacteria detection.. Cellular and molecular life sciences : CMLS. 61(5):537-46.
  4. Gobert V, Gottar M, Matskevich AA, Rutschmann S, Royet J, Belvin M, Hoffmann JA, Ferrandon D.  2003.  Dual activation of the Drosophila toll pathway by two pattern recognition receptors.. Science (New York, N.Y.). 302(5653):2126-30.
  5. Ligoxygakis P, Pelte N, Ji C, Leclerc V, Duvic B, Belvin M, Jiang H, Hoffmann JA, Reichhart J-M.  2002.  A serpin mutant links Toll activation to melanization in the host defence of Drosophila.. The EMBO journal. 21(23):6330-7.
  6. Ligoxygakis P, Pelte N, Hoffmann JA, Reichhart J-M.  2002.  Activation of Drosophila Toll during fungal infection by a blood serine protease.. Science (New York, N.Y.). 297(5578):114-6.
  7. Pelte N, Robertson AS, Zou Z, Belorgey D, Dafforn TR, Jiang H, Lomas D, Reichhart J-M, Gubb D.  2006.  Immune challenge induces N-terminal cleavage of the Drosophila serpin Necrotic.. Insect biochemistry and molecular biology. 36(1):37-46.
  8. Bischoff V, Vignal C, Boneca IG, Michel T, Hoffmann JA, Royet J.  2004.  Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria.. Nature immunology. 5(11):1175-80.
  9. Valanne S, Wang J-H, Rämet M.  2011.  The Drosophila Toll signaling pathway.. Journal of immunology (Baltimore, Md. : 1950). 186(2):649-56.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila Notch Signalling pathway

Summary: 

Notch signaling is involved in the modulation of Twist expression and the subdivision of the mesoderm into high and low domain of Twist. The binding of Delta leads to the cleavage and the release of the Notch intracellular domain NICD. During mesoderm specification, NICD can inhibit Twist by forming a complex with EMC, or in combination with Enhancer of split and Suppressor of hairless proteins. In this regard, we modeled the effect of Notch pathway on Twist expression. Our defined initial states reproduce biological data during mesoderm specification. When Delta is ON (high or medium signaling), the level of Twist expression can decrease from 2 to 1 or 0. When Delta is OFF (no signaling), Twist is expressed at its maximal level 2. For more details on Notch signalling pathway and it's role on Twist expression regulation during Drosophila development, see [1]; [2]; [3]; [4]; [5].


References

  1. Bate M, Rushton E.  1993.  Myogenesis and muscle patterning in Drosophila.. Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie. 316(9):1047-61.
  2. Baylies MK, Bate M.  1996.  twist: a myogenic switch in Drosophila.. Science (New York, N.Y.). 272(5267):1481-4.
  3. Fuerstenberg S, Giniger E.  1998.  Multiple roles for notch in Drosophila myogenesis.. Developmental biology. 201(1):66-77.
  4. Tapanes-Castillo A, Baylies MK.  2004.  Notch signaling patterns Drosophila mesodermal segments by regulating the bHLH transcription factor twist.. Development (Cambridge, England). 131(10):2359-72.
  5. Ciglar L, Furlong EEM.  2009.  Conservation and divergence in developmental networks: a view from Drosophila myogenesis.. Current opinion in cell biology. 21(6):754-60.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila JAK/STAT Signalling pathway

Summary: 

In Drosophila, three secreted ligands (OS, UPD2 and UPD3) have been identified for the JAK/STAT pathway. Their binding to the receptor dome induces its homo-dimerization, enabling hop to phosphorylate specific tyrosine residues of the receptor. Consequently, STAT92E is also phosphorylated by HOP, leading to his homo-dimerization and nuclear translocation. In the nucleus, STAT92E binds to target DNA sequences and acts as an activator of transcription of several target genes ([1]). During Drosophila development, the JAK/STAT pathway is involved in embryonic segmentation, eye development, cell growth, haematopoiesis, and sex determination ([2]; [3]). JAK/STAT signalling also plays important roles during spermatogenesis ([4]) and oogenesis ([5]; [6]; [3]). To study the dynamic of the pathway, we define a set of initial states representative of in vivo situations during JAK/STAT signalling. More precisely, we define a three initial states corresponding to pathway signalling (binding of OS or UPD2 or UPD3) and two initial states corresponding to pathway signalling in the presence of an inhibitor (SOCS44A or BRWD3) and one initial state corresponding to non signalling conditions (no binding of ligands).


References

  1. Hou XS, Perrimon N.  1997.  The JAK-STAT pathway in Drosophila.. Trends in genetics : TIG. 13(3):105-10.
  2. Luo H, Dearolf CR.  2001.  The JAK/STAT pathway and Drosophila development.. BioEssays : news and reviews in molecular, cellular and developmental biology. 23(12):1138-47.
  3. Johnson AN, Mokalled MH, Haden TN, Olson EN.  2011.  JAK/Stat signaling regulates heart precursor diversification in Drosophila. Development. 138(21):4627-4638.
  4. Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT.  2001.  Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue.. Science (New York, N.Y.). 294(5551):2542-5.
  5. Denef N, Schüpbach T.  2003.  Patterning: JAK-STAT signalling in the Drosophila follicular epithelium.. Current biology : CB. 13(10):R388-90.
  6. Xi R, McGregor JR, Harrison DA.  2003.  A gradient of JAK pathway activity patterns the anterior-posterior axis of the follicular epithelium.. Developmental cell. 4(2):167-77.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila FGF Signalling pathway

Summary: 

Drosophila genome encodes two FGF receptors, HTL (Heartless) and BTL (Breathless), which are required for the morphogenesis of different tissues. BTL is expressed in the tracheae, while HTL is expressed in embryonic mesoderm and was first identified because of its essential role in heart development. BTL ligand, BNL is encoded by the branchless gene ([1]). THS (Thisbe) and PYR (Pyramus) function in a partially redundant fashion to activate heartless (htl). Upon ligand binding receptor dimerization triggers the canonical DRK/SOS/RAS/RAF/DSOR1/RL pathway. In contrast with other RTKs, Stumps is needed to trigger signal transduction (see [2]; [3]). Stumps is a cytoplasmic protein expressed in cells also expressing the FGF receptors. The presence of an ankyrin repeat, a coiled-coil structure and many tyrosines suggests that Stumps could bind SH2 domains of proteins such as DRK or CSW ([4]). As a result, DRK recruits the guanine nucleotide exchange factor SOS (Son of sevenless), which catalyzes the exchange of GDP bound to RAS for GTP. Activated RAS then promotes the activation of RAF (Pole hole), DSOR1, and eventually that of RL (Rolled). RL can activate transcription through the inactivation of transcriptional co-repressors such as Anterior Open (AOP), as well as through the activation of transcriptional activators such as PNT (Pointed, with two forms denote by suffixes P1 and P2) ([5]; [6]). The negative regulator STY (Sprouty) acts downstream of SOS but upstream of RAS and RAF, by recruiting GAP1 and blocking the ability of DRK to bind to its positive effector. Our model enables the simulation of pathway responses to different ligand combinations. In this regard, we define four initial states to simulate different behavior of the pathway. The first initial state reproduces the signalling through the receptor HTL (bound by Pyr and Ths), the second initial state corresponds to the signalling through the receptor BTL, the third initial state corresponds to the involvement of the inhibitor Sprouty during signalling conditions and the fourth initial state corresponds to the absence of signalling (no ligands binding). Each of these initial states lead to a specific stable state representative of in vivo conditions.


References

Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila Wg Signalling pathway

Summary: 

In the absence of WG, the protein complex composed by Axin, Shaggy (SGG or ZW3) and APC sequesters and ubiquitinilates Armadillo, leading to a Slmb-dependant degradation by the proteasome. In the absence of ARM, PAN binds to GRO to repress WG targets. Binding of Wingless to Arrow (ARR) or Frizzled (FZ) triggers a set of reactions, starting with the activation of Dishevelled, which in turn inhibits the AXN-SGG-APC complex. This leads (with the help of HIPK) to the accumulation and the stabilisation of ARM. Next, ARM translocates into the nucleus and binds Pangolin (PAN). Then, the ARM/PAN complex with the help of other cofactors (LGS, Nej, Pygo and Hyx) activates the transcription of WG targets. During some patterning processes as in wing disc, Nemo can inhibit PAN and thereby controls the level of WG signalling. To study dynamically the WG signalling pathway, we define two initial states corresponding to the binding of WG ligand and to the absence of binding condition. From these two initial states, we compute the resulting stable states recapitulating the activation or the non activation of the pathway, respectively. For more details on Dpp signalling pathway regulation see [1]; [2]; [3]; [4]; [5].


References

  1. Klingensmith J, Nusse R.  1994.  Signaling by wingless in Drosophila.. Developmental biology. 166(2):396-414.
  2. Michelson AM.  2003.  Running interference for hedgehog signaling.. Science's STKE : signal transduction knowledge environment. 2003(192):PE30.
  3. Perrimon N, Pitsouli C, Shilo B-Z.  2012.  Signaling mechanisms controlling cell fate and embryonic patterning.. Cold Spring Harbor perspectives in biology. 4(8):a005975.
  4. Swarup S, Verheyen EM.  2012.  Wnt/Wingless signaling in Drosophila.. Cold Spring Harbor perspectives in biology. 4(6)
  5. Tauc HM, Mann T, Werner K, Pandur P.  2012.  A role for Drosophila Wnt-4 in heart development.. Genesis (New York, N.Y. : 2000). 50(6):466-81.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY
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