Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord.
We have assembled a network of cell-fate determining transcription factors that play a key role in the specification of the ventral neuronal subtypes of the spinal cord on the basis of published transcriptional interactions. Asynchronous Boolean modelling of the network was used to compare simulation results with reported experimental observations. Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where the transcription factors were overexpressed. Furthermore the network predicted the inhibition of Irx3 by Nkx2.2 and this prediction was tested experimentally. Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord. The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.
Biotalentum Ltd., Gödöllö, Hungary.
Anna
A
Lovrics
Biotalentum Ltd., Gödöllö, Hungary.
Yu
Y
Gao
Biotalentum Ltd., Gödöllö, Hungary.
Bianka
B
Juhász
Biotalentum Ltd., Gödöllö, Hungary; Molecular Animal Biotechnology Laboratory, Szent Istvan University, Gödöllö, Hungary.
István
I
Bock
Oxford Centre for Collaborative Applied Mathematics, Mathematical Institute, University of Oxford, Oxford, United Kingdom.
Helen M
HM
Byrne
Biotalentum Ltd., Gödöllö, Hungary; Molecular Animal Biotechnology Laboratory, Szent Istvan University, Gödöllö, Hungary; Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
András
A
Dinnyés
Biotalentum Ltd., Gödöllö, Hungary; Institute of Science and Technology, Klosterneuburg, Austria.
Krisztián A
KA
Kovács
D003198:Computer Simulation; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D013116:Spinal Cord / Q000196:embryology*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D008156:Luciferases