Abstract
Cell migration is a key component in development, homeostasis, immune function, and pathology. It is important to understand the molecular activity that allows some cells to migrate. Drosophila melanogaster is a useful model system because its genes are largely conserved with humans and it is straightforward to study biologically. The well-conserved transcriptional regulator Signal Transducer and Activator of Transcription (STAT) promotes cell migration, but its signaling is modulated by downstream targets Apontic (APT) and Slow Border Cells (SLBO). Inhibition of STAT activity by APT and cross-repression of APT and SLBO determines whether an epithelial cell in the Drosophila egg chamber becomes motile or remains stationary. Through mathematical modeling and analysis, we examine how the interaction of STAT, APT, and SLBO creates bistability in the Janus Kinase (JAK)/STAT signaling pathway. In this paper, we update and analyze earlier models to represent mechanistically the processes of the JAK/STAT pathway. We utilize parameter, bifurcation, and phase portrait analyses, and make reductions to the system to produce a minimal three-variable quantitative model. We analyze the manifold between migratory and stationary steady states in this minimal model and show that when the initial conditions of our model are near this manifold, cell migration can be delayed.
Highlights
The acquisition of cellular migration plays a critical role in both normal and pathological development
We focus on the protein products from two genes activated by Signal Transducer and Activator of Transcription (STAT): Apontic (APT) and Slow Border Cells (SLBO)
We show the repressed state for the slbo gene induced by APT contributes to bistability (Starz-Gaiano et al, 2008)
Summary
The acquisition of cellular migration plays a critical role in both normal and pathological development. Depending on the strength of the UPD signal and the level of STAT activity, each border cell can become motile (SLBO dominates) or remain stationary (APT dominates). We apply this model in the interesting case of controlling microRNAmediated degradation of stat mRNA via APT and show that delays in STAT activation, even to the point of activation failure within a biophysical time span, are possible due to the proximity of the critical UPD level to a limit point bifurcation. We conclude with possible experimentation that could test and improve our model
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