Completion of several genome projects has produced a wealth of information about the genes that make up the organisms investigated. This knowledge now needs to be enhanced with information on how individual genes work together to produce higher order biological phenomena. Interactions between gene products are most prevalent during development of multicellular organisms when cells send chemical cues to neighboring cells to induce or guide fate patterning. Correct cell fate specification is required for development of functional organs.

A specific example of robust fate specification is the cell patterning of vulval precursor cells during development of nematode C. elegans larvae. This process is guided by a long-range gradient in the soluble factor LIN-3 and by short-range direct interactions between neighboring cells mediated by the Notch-like receptor, LIN-12. Genetic evidence shows that these two fate patterning signals are coupled: lateral cell-cell interactions inhibit LIN-3 mediated signaling, whereas LIN-3 regulates the extent of lateral signaling.

This work sought to elucidate the quantitative implications of the topology of network interactions using mathematical modeling. We developed a kinetic model of LIN-3/LIN-12 mediated signaling in the vulval precursor cell array. We show that coupling LIN-3 and LIN-12 signaling pathways amplifies the cellular perception of LIN-3 gradient and polarizes lateral signaling, both of which enhance fate segregation beyond that achieved by an uncoupled system. We are currently experimentally testing the prediction that LIN-3 gradient is amplified in response to lateral signaling using a fluorescent reporter responsive to LIN-3 signaling that has been chromosomally integrated in worms.

Furthermore, the results of an extensive parameter-domain sweep show that experimentally observed mutant phenotypes as well as the wild-type phenotype are among the most prevalent phenotypes predicted by the model. In silico mutants identified require the same mutations as their experimental counterparts. Moreover, our model identifies new ways of producing known experimental mutants as well as specifies which mutations should be performed to obtain novel mutants that could be tested in the lab.

Since both LIN-3 and LIN-12 signaling components are conserved biological information processing pathways in worms, flies and mammals, this study provides an understanding about basic mechanisms guiding developmental steps of simple and complex organisms.

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