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BIOMD0000000398 - Sivakumar2011_NeuralStemCellDifferentiation_Crosstalk

 

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Reference Publication
Publication ID: 21978399
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
OMICS 2011 Oct; 15(10): 729-737
Bioinformatics Facility, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.  [more]
Model
Original Model: BIOMD0000000398.xml.origin
Submitter: Vijayalakshmi Chelliah
Submission ID: MODEL1111020000
Submission Date: 02 Nov 2011 14:52:52 UTC
Last Modification Date: 02 Jun 2014 14:22:14 UTC
Creation Date: 02 Nov 2011 14:54:21 UTC
Encoders:  Vijayalakshmi Chelliah
   KC Sivakumar
set #1
bqbiol:isVersionOf Gene Ontology canonical Wnt signaling pathway
Gene Ontology Notch signaling pathway
Gene Ontology smoothened signaling pathway
Gene Ontology epidermal growth factor receptor signaling pathway
Gene Ontology stem cell differentiation
bqbiol:occursIn Cell Type Ontology CL:0000047
set #2
bqbiol:hasTaxon Taxonomy Mammalia
set #3
bqmodel:isDerivedFrom BioModels Database Sivakumar2011_EGFReceptorSignalingPathway
BioModels Database Sivakumar2011_HedgehogSignalingPathway
BioModels Database Sivakumar2011_NotchSignalingPathway
BioModels Database Sivakumar2011_WntSignalingPathway
Notes
Sivakumar2011_NeuralStemCellDifferentiation_Crosstalk
This model is generated by integrating BIOMD0000000394 (EGFR), BIOMD0000000395 (Hedgehog), BIOMD0000000396 (Notch) and BIOMD0000000397 (Wnt), to investigate the signalling crosstalk between the four pathways.

This model is described in the article:

Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
OMICS 2011 Oct; 15(10): 729-737

Abstract:

The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 21978399 Submission Date: 02 Nov 2011 14:52:52 UTC Last Modification Date: 02 Jun 2014 14:22:14 UTC Creation Date: 02 Nov 2011 14:54:21 UTC
Mathematical expressions
Reactions
re29 re31 re32 re33
re36 re37 re38 re40
re42 re43 re34 re35
Physical entities
Compartments Species
default NICD Notch Notch TM
Gamma secretase DAPT RBP-jk
Complex NICD-RBP Shh Ptch1
Complex Shh Ptch1 smo SAG
EGF EGFR Complex EGF-EGFR
Erlotinib Wnt Frzzl
Complex Wnt-Frzzl Dishevelled FRAT-CK2
Complex Dishevelled-FRAT-CK2 GSK3B Beta-catenin
Complex GSK3B-Bcatenin 6 bromoindirubin 3`oxime  
nucleus Hes-1    
Global parameters
kV_re29_s60 kM_re29_s60_s57 kG_s57 kM_re29_s60_s53
kG_s53 kM_re29_s60_s58 kG_s58 kI_re29_s61
kass_re31 kdiss_re31 kass_re32 kdiss_re32
kass_re33 kdiss_re33 kass_re36 kdiss_re36
kI_re36_s101 kass_re37 kdiss_re37 kass_re38
kdiss_re38 kcatp_re40 kcatn_re40 kM_re40_s124
ki_re40_s124 kass_re42 kdiss_re42 kI_re42_s147
kI_re42_s135 kass_re43 kdiss_re43 kass_re34_s85
kdiss_re34_s85 kass_re34_s89 kdiss_re34_s89 kass_re35_s89
kdiss_re35_s89      
Reactions (12)
 
 re29 [Notch] ↔ [NICD] + [Notch TM];   {Gamma secretase} , {DAPT}
 
 re31 [NICD] + [RBP-jk] ↔ [Complex NICD-RBP];  
 
 re32 [Complex NICD-RBP] ↔ [Hes-1];  
 
 re33 [Shh] + [Ptch1] ↔ [Complex Shh Ptch1];  
 
 re36 [EGF] + [EGFR] ↔ [Complex EGF-EGFR];   {Erlotinib}
 
 re37 [Complex EGF-EGFR] ↔ [Hes-1];  
 
 re38 [Wnt] + [Frzzl] ↔ [Complex Wnt-Frzzl];  
 
 re40 [Dishevelled] + [FRAT-CK2] ↔ [Complex Dishevelled-FRAT-CK2];   {Complex Wnt-Frzzl}
 
 re42 [GSK3B] + [Beta-catenin] ↔ [Complex GSK3B-Bcatenin];   {6 bromoindirubin 3`oxime} , {Complex Dishevelled-FRAT-CK2}
 
 re43 [Beta-catenin] ↔ [Hes-1];  
 
 re34 [smo] ↔ [smo];   {Complex Shh Ptch1} , {SAG}
 
 re35 [smo] ↔ [Hes-1];   {SAG}
 
   Spatial dimensions: 3.0  Compartment size: 1.0
 
 NICD
Compartment: default
Initial amount: 0.0
 
 Notch
Compartment: default
Initial amount: 5.0
 
 Notch TM
Compartment: default
Initial amount: 0.0
 
 Gamma secretase
Compartment: default
Initial amount: 5.0
 
 DAPT
Compartment: default
Initial amount: 100.0
 
 RBP-jk
Compartment: default
Initial amount: 5.0
 
 Complex NICD-RBP
Compartment: default
Initial amount: 0.0
 
 Shh
Compartment: default
Initial amount: 5.0
 
 Ptch1
Compartment: default
Initial amount: 5.0
 
 Complex Shh Ptch1
Compartment: default
Initial amount: 0.0
 
 smo
Compartment: default
Initial amount: 5.0
 
 SAG
Compartment: default
Initial amount: 0.0
 
 EGF
Compartment: default
Initial amount: 5.0
 
 EGFR
Compartment: default
Initial amount: 5.0
 
 Complex EGF-EGFR
Compartment: default
Initial amount: 0.0
 
 Erlotinib
Compartment: default
Initial amount: 100.0
 
 Wnt
Compartment: default
Initial amount: 5.0
 
 Frzzl
Compartment: default
Initial amount: 5.0
 
 Complex Wnt-Frzzl
Compartment: default
Initial amount: 0.0
 
 Dishevelled
Compartment: default
Initial amount: 5.0
 
 FRAT-CK2
Compartment: default
Initial amount: 5.0
 
 Complex Dishevelled-FRAT-CK2
Compartment: default
Initial amount: 0.0
 
 GSK3B
Compartment: default
Initial amount: 5.0
 
 Beta-catenin
Compartment: default
Initial amount: 5.0
 
 Complex GSK3B-Bcatenin
Compartment: default
Initial amount: 0.0
 
 6 bromoindirubin 3`oxime
Compartment: default
Initial amount: 100.0
 
 nucleus Spatial dimensions: 3.0  Compartment size: 1.0
 
 Hes-1
Compartment: nucleus
Initial amount: 0.0
 
Global Parameters (37)
 
   kV_re29_s60
Value: 1.0
Constant
 
   kM_re29_s60_s57
Value: 1.0
Constant
 
   kG_s57
Value: 1.0
Constant
 
   kM_re29_s60_s53
Value: 1.0
Constant
 
   kG_s53
Value: 1.0
Constant
 
   kM_re29_s60_s58
Value: 1.0
Constant
 
   kG_s58
Value: 1.0
Constant
 
   kI_re29_s61
Value: 1.0
Constant
 
   kass_re31
Value: 1.0
Constant
 
   kdiss_re31
Value: 1.0
Constant
 
   kass_re32
Value: 1.0
Constant
 
   kdiss_re32
Value: 1.0
Constant
 
   kass_re33
Value: 1.0
Constant
 
   kdiss_re33
Value: 1.0
Constant
 
   kass_re36
Value: 1.0
Constant
 
   kdiss_re36
Value: 1.0
Constant
 
   kI_re36_s101
Value: 1.0
Constant
 
   kass_re37
Value: 1.0
Constant
 
   kdiss_re37
Value: 1.0
Constant
 
   kass_re38
Value: 1.0
Constant
 
   kdiss_re38
Value: 1.0
Constant
 
   kcatp_re40
Value: 1.0
Constant
 
   kcatn_re40
Value: 1.0
Constant
 
   kM_re40_s124
Value: 1.0
Constant
 
   ki_re40_s124
Value: 1.0
Constant
 
   kass_re42
Value: 1.0
Constant
 
   kdiss_re42
Value: 1.0
Constant
 
   kI_re42_s147
Value: 1.0
Constant
 
   kI_re42_s135
Value: 1.0
Constant
 
   kass_re43
Value: 1.0
Constant
 
   kdiss_re43
Value: 1.0
Constant
 
   kass_re34_s85
Value: 1.0
Constant
 
   kdiss_re34_s85
Value: 1.0
Constant
 
   kass_re34_s89
Value: 1.0
Constant
 
   kdiss_re34_s89
Value: 1.0
Constant
 
   kass_re35_s89
Value: 1.0
Constant
 
   kdiss_re35_s89
Value: 1.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000398

Curator's comment: (updated: 02 Nov 2011 14:54:07 GMT)

Figure 3 of the reference publication has been reproduced here. The model was simulated using Copasi v4.7 (Build 34).

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