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Abstract
How cells in developing organisms interpret the quantitative information contained in morphogen gradients is an open question. Here we address this question using a novel integrative approach that combines quantitative measurements of morphogen-induced gene expression at single-mRNA resolution with mathematical modelling of the induction process. We focus on the induction of Notch ligands by the LIN-3/EGF morphogen gradient during vulva induction in Caenorhabditis elegans. We show that LIN-3/EGF-induced Notch ligand expression is highly dynamic, exhibiting an abrupt transition from low to high expression. Similar transitions in Notch ligand expression are observed in two highly divergent wild C. elegans isolates. Mathematical modelling and experiments show that this transition is driven by a dynamic increase in the sensitivity of the induced cells to external LIN-3/EGF. Furthermore, this increase in sensitivity is independent of the presence of LIN-3/EGF. Our integrative approach might be useful to study induction by morphogen gradients in other systems.
Highlights
How cells in developing organisms interpret the quantitative information contained in morphogen gradients is an open question
The external LIN-3 gradient is amplified into an all-or-nothing difference in signalling between vulva precursor cells (VPCs), with EGF/RAS signalling and Notch ligand expression restricted to P6.p (1° fate) and high LIN-12/ Notch activity in P(5,7).p (2° fate)
These results indicated that the lag-2 and apx-1 expression patterns, as observed by single molecule fluorescence in situ hybridization (smFISH), reflected their induction by LIN-3
Summary
How cells in developing organisms interpret the quantitative information contained in morphogen gradients is an open question. How cells in developing embryos interpret external signals to make robust cell fate decisions is still an open question This is challenging for the induction of spatial cell fate patterns by morphogen gradients, where induced cells do not just respond to the absence or presence of a signal, but rather to its exact local concentration[1,2,3,4]. Quantitative measurements can be used to test and constrain mathematical models of the underlying gene regulatory network In this way, one can identify in a systematic manner which parameters in the model are essential to explain the observed dynamics. One can identify in a systematic manner which parameters in the model are essential to explain the observed dynamics We use such a quantitative approach to study C. elegans vulva induction, a classical model of spatial cell fate patterning by a morphogen gradient. A reporter for egl-17 was induced by LIN-3 in a graded manner, that is, decreasing with
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