Abstract
The vulva of Caenorhabditis elegans has been long used as an experimental model of cell differentiation and organogenesis. While it is known that the signaling cascades of Wnt, Ras/MAPK, and NOTCH interact to form a molecular network, there is no consensus regarding its precise topology and dynamical properties. We inferred the molecular network, and developed a multivalued synchronous discrete dynamic model to study its behavior. The model reproduces the patterns of activation reported for the following types of cell: vulval precursor, first fate, second fate, second fate with reversed polarity, third fate, and fusion fate. We simulated the fusion of cells, the determination of the first, second, and third fates, as well as the transition from the second to the first fate. We also used the model to simulate all possible single loss- and gain-of-function mutants, as well as some relevant double and triple mutants. Importantly, we associated most of these simulated mutants to multivulva, vulvaless, egg-laying defective, or defective polarity phenotypes. The model shows that it is necessary for RAL-1 to activate NOTCH signaling, since the repression of LIN-45 by RAL-1 would not suffice for a proper second fate determination in an environment lacking DSL ligands. We also found that the model requires the complex formed by LAG-1, LIN-12, and SEL-8 to inhibit the transcription of eff-1 in second fate cells. Our model is the largest reconstruction to date of the molecular network controlling the specification of vulval precursor cells and cell fusion control in C. elegans. According to our model, the process of fate determination in the vulval precursor cells is reversible, at least until either the cells fuse with the ventral hypoderm or divide, and therefore the cell fates must be maintained by the presence of extracellular signals.
Highlights
Caenorhabditis elegans is a nematode used extensively as a model organism for study in the areas of genomics, cell biology, neuroscience, aging, genetics, developmental biology, and cell differentiation (Hodgkin, 2005; Herman, 2006; Golden and Melov, 2007; Hobert, 2010)
Four interactions are predictions that are supported by our modeling effort; namely, (1) RAL-1 activates the protein complex that allows the lateral signal targets to be expressed, (2) the self activation of LIN-39 transcription requires LIN-39 to be phosphorylated by MPK-1, (3) the complex formed by LAG-1, LIN-12 and SEL-8 inhibits the transcription of eff-1 in the second fate cells, and (4) the Hox factors MAB-5 and CEH-13 inhibit vulval fate determination by rendering the cofactors UNC-62 and CEH-20 unavailable to LIN-39
STATIONARY PATTERNS OF ACTIVATION The analysis of the dynamical behavior shows that the network has 11 fixed point attractors (Figure 3), all of which can be interpreted as the stable patterns of molecular activation possible for different vulval cells
Summary
Caenorhabditis elegans is a nematode used extensively as a model organism for study in the areas of genomics, cell biology, neuroscience, aging, genetics, developmental biology, and cell differentiation (Hodgkin, 2005; Herman, 2006; Golden and Melov, 2007; Hobert, 2010). The vulva is a small organ with the main functions of copulation and egg laying. It is formed by a stack of seven different epithelial rings, namely (in ventral-todorsal order): vulA, vulB1, vulB2, vulC, vulD, vulE, and vulF, containing a total of 22 nuclei (Figure 1). Each of these rings is either a single tetranucleate syncytium, a binucleate syncytium (vulD) or two half-ring binucleate syncytia (vulB1 and vulB2). This organ interacts with muscles, nerves, the gonad, and the ventral hypodermis (Lints and Hall, 2009)
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