Abstract
The Notch signaling pathway controls numerous cell fate decisions during development and adulthood through diverse mechanisms. Thus, whereas it functions as an oscillator during somitogenesis, it can mediate an all-or-none cell fate switch to influence pattern formation in various tissues during development. Furthermore, while in some contexts continuous Notch signaling is required, in others a transient Notch signal is sufficient to influence cell fate decisions. However, the signaling mechanisms that underlie these diverse behaviors in different cellular contexts have not been understood. Notch1 along with two downstream transcription factors hes1 and RBP-Jk forms an intricate network of positive and negative feedback loops, and we have implemented a systems biology approach to computationally study this gene regulation network. Our results indicate that the system exhibits bistability and is capable of switching states at a critical level of Notch signaling initiated by its ligand Delta in a particular range of parameter values. In this mode, transient activation of Delta is also capable of inducing prolonged high expression of Hes1, mimicking the “ON” state depending on the intensity and duration of the signal. Furthermore, this system is highly sensitive to certain model parameters and can transition from functioning as a bistable switch to an oscillator by tuning a single parameter value. This parameter, the transcriptional repression constant of hes1, can thus qualitatively govern the behavior of the signaling network. In addition, we find that the system is able to dampen and reduce the effects of biological noise that arise from stochastic effects in gene expression for systems that respond quickly to Notch signaling.This work thus helps our understanding of an important cell fate control system and begins to elucidate how this context dependent signaling system can be modulated in different cellular settings to exhibit entirely different behaviors.
Highlights
Cells continuously receive signals from their microenvironments – including factors present in the extracellular matrix, soluble media, and surrounding cells – which collectively influence cell function and behavior via activating intracellular signal transduction and gene regulation networks
At low levels of Delta signal, basal levels of Hes1 are maintained in the cell (‘‘OFF’’ state), but as the Delta signal strength is increased beyond a threshold level, it stimulates the production of Hes1, which is maintained at high levels (‘‘ON’’ state) through the concerted regulation of the Notch1-RBP-Jk-Hes1 network (Fig. 2B)
The Notch signaling system is an evolutionarily conserved network that functions in multiple organs to orchestrate cell fate specification [63,64,65] in a context dependent manner. It can function as a binary cell fate switch at the individual cell level [16,17], whereas in other situations cell-cell contact dependent Notch signaling can result in pattern formation in an array of cells [14,15], and in yet other contexts it can function as a biological clock to govern pattern formation and differentiation during somitogenesis [27,28,29]
Summary
Cells continuously receive signals from their microenvironments – including factors present in the extracellular matrix, soluble media, and surrounding cells – which collectively influence cell function and behavior via activating intracellular signal transduction and gene regulation networks These networks generally involve complex, nonlinear interactions of proteins, such as phosphorylation cascades (reviewed in [1]) and second messenger signaling systems [2], whose structures feature positive and negative feedback loops, feed-forward interactions, signal amplification, and cross-talk with other pathways [3]. Notch is a signaling system required for numerous critical cell fate specification events during the development of the nervous system, hematopoietic system, eye, and skin [7,8,9,10,11] The receptor for this pathway is the single pass transmembrane protein Notch that, when bound by its ligands Delta or Jagged, undergoes a series of cleavage events to release its intracellular domain (NICD) [9,12]. We have focused primarily on the Notch signaling pathway
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