title: A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
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.
authors: Bioinformatics Facility, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
authors: Krishnankutty Chandrika
authors: KC
authors: Sivakumar
authors: Sivadasan Bindu
authors: SB
authors: Dhanesh
authors: Sekar
authors: S
authors: Shobana
authors: Jackson
authors: J
authors: James
authors: Sathish
authors: S
authors: Mundayoor
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D003198:Computer Simulation; D004815:Epidermal Growth Factor / Q000502:physiology*; D000069347:Erlotinib Hydrochloride; D015870:Gene Expression; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction; D049490:Systems Biology; D000072056:Transcription Factor HES-1; D051153:Wnt Proteins / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D051153:Wnt Proteins; C078493:HES1 protein, human