Abstract
Gene regulatory networks have been conserved during evolution. The Drosophila wing and the vertebrate hindbrain share the gene network involved in the establishment of the boundary between dorsal and ventral compartments in the wing and adjacent rhombomeres in the hindbrain. A positive feedback-loop between boundary and non-boundary cells and mediated by the activities of Notch and Wingless/Wnt-1 leads to the establishment of a Notch dependent organizer at the boundary. By means of a Systems Biology approach that combines mathematical modeling and both in silico and in vivo experiments in the Drosophila wing primordium, we modeled and tested this regulatory network and present evidence that a novel property, namely refractoriness to the Wingless signaling molecule, is required in boundary cells for the formation of a stable dorsal-ventral boundary. This new property has been validated in vivo, promotes mutually exclusive domains of Notch and Wingless activities and confers stability to the dorsal-ventral boundary. A robustness analysis of the regulatory network complements our results and ensures its biological plausibility.
Highlights
As occurs in most biological phenomena, gene expression underlies morphogenesis
By means of gene expression, cells specialize for shaping and organizing tissues. This feature poses the interesting question of how cell fate is determined, i.e. how a given cell and its progeny ‘‘know’’ what genes should and should not be expressed in order to perform a particular task. The latter immediately suggests the concept of information and reveals an additional function performed by gene expression and regulated by cell interactions: gene expression provides positional information [1]
Forced expression of Cut in non-boundary cells represses the expression of Wg target genes (Figure 4D and Figure S1). These results indicate that Cut is required and sufficient to inhibit Wg target gene expression in boundary cells downstream of Notch
Summary
By means of gene expression, cells specialize for shaping and organizing tissues This feature poses the interesting question of how cell fate is determined, i.e. how a given cell and its progeny ‘‘know’’ what genes should and should not be expressed in order to perform a particular task. Genetic activity establishes an expression pattern, a ‘‘map’’, by means of which cell fate is determined depending on the relative positions of cells inside the tissue. This orchestrated plan sets up a dynamical coordinate system that links the gene expression pattern, genotype, to the resulting biological structure, phenotype
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