title: Logic programming to predict cell fate patterns and retrodict genotypes in organogenesis.
abstract: Caenorhabditis elegans vulval development is a paradigm system for understanding cell differentiation in the process of organogenesis. Through temporal and spatial controls, the fate pattern of six cells is determined by the competition of the LET-23 and the Notch signalling pathways. Modelling cell fate determination in vulval development using state-based models, coupled with formal analysis techniques, has been established as a powerful approach in predicting the outcome of combinations of mutations. However, computing the outcomes of complex and highly concurrent models can become prohibitive. Here, we show how logic programs derived from state machines describing the differentiation of C. elegans vulval precursor cells can increase the speed of prediction by four orders of magnitude relative to previous approaches. Moreover, this increase in speed allows us to infer, or 'retrodict', compatible genomes from cell fate patterns. We exploit this technique to predict highly variable cell fate patterns resulting from dig-1 reduced-function mutations and let-23 mosaics. In addition to the new insights offered, we propose our technique as a platform for aiding the design and analysis of experimental data.
authors: Microsoft Research, 21 Station Road, Cambridge CB1 2FB, UK benhall@microsoft.com.
authors: Benjamin A
authors: BA
authors: Hall
authors: Microsoft Research, One Microsoft Way, Redmond, WA 98052, USA.
authors: Ethan
authors: E
authors: Jackson
authors: Institute of Molecular Life Sciences, University of Zurich, Zurich 8057, Switzerland.
authors: Alex
authors: A
authors: Hajnal
authors: Microsoft Research, 21 Station Road, Cambridge CB1 2FB, UK Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK jasmin.fisher@microsoft.com.
authors: Jasmin
authors: J
authors: Fisher
mesh_terms: D000465:Algorithms; D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000502:physiology; D019070:Cell Lineage; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D049751:Genome, Helminth; D005838:Genotype; D008957:Models, Genetic; D009154:Mutation; D038081:Organogenesis; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014844:Vulva / Q000196:embryology
chemical_list: D029742:Caenorhabditis elegans Proteins; D051880:Receptors, Notch; D066246:ErbB Receptors; C085873:let-23 protein, C elegans
keywords: C. elegans; development; executable modelling; logic programming; organogenesis