Article

Negative Feedback Enhances Robustness in the Yeast Polarity Establishment Circuit

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Cell (Impact Factor: 33.12). 04/2012; 149(2):322-33. DOI: 10.1016/j.cell.2012.03.012
Source: PubMed

ABSTRACT Many cells undergo symmetry-breaking polarization toward a randomly oriented "front" in the absence of spatial cues. In budding yeast, such polarization involves a positive feedback loop that enables amplification of stochastically arising clusters of polarity factors. Previous mathematical modeling suggested that, if more than one cluster were amplified, the clusters would compete for limiting resources and the largest would "win," explaining why yeast cells always make one and only one bud. Here, using imaging with improved spatiotemporal resolution, we show the transient coexistence of multiple clusters during polarity establishment, as predicted by the model. Unexpectedly, we also find that initial polarity factor clustering is oscillatory, revealing the presence of a negative feedback loop that disperses the factors. Mathematical modeling predicts that negative feedback would confer robustness to the polarity circuit and make the kinetics of competition between polarity factor clusters relatively insensitive to polarity factor concentration. These predictions are confirmed experimentally.

Download full-text

Full-text

Available from: Chi-Fang Wu, Feb 25, 2015
0 Followers
 · 
125 Views
  • Source
    • "It is thus possible that positive and negative feedback is operating in the HSN neuron on UNC-40 and that UNC-40 (A1056V) and UNC-53 alter these feedback mechanisms such that more stable UNC-40 clusters can be detected. Positive and negative feedback might be differently tuned in the HSN neuron to provide a cell type– specific polarity response (Novák and Tyson, 2008; Howell et al., 2012), and thus oscillations in UNC-40 cluster formation might be absent or more difficult to detect. Given that real-time imaging techniques have not yet been developed in the HSN neuron (Xu et al., 2009; Kulkarni et al., 2013), it is also possible that oscillations in UNC-40 clustering are present but have yet to be resolved. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The receptor deleted in colorectal cancer (DCC) directs dynamic polarizing activities in animals toward its extracellular ligand netrin. How DCC polarizes toward netrin is poorly understood. By performing live-cell imaging of the DCC orthologue UNC-40 during anchor cell invasion in Caenorhabditis elegans, we have found that UNC-40 clusters, recruits F-actin effectors, and generates F-actin in the absence of UNC-6 (netrin). Time-lapse analyses revealed that UNC-40 clusters assemble, disassemble, and reform at periodic intervals in different regions of the cell membrane. This oscillatory behavior indicates that UNC-40 clusters through a mechanism involving interlinked positive (formation) and negative (disassembly) feedback. We show that endogenous UNC-6 and ectopically provided UNC-6 orient and stabilize UNC-40 clustering. Furthermore, the UNC-40-binding protein MADD-2 (a TRIM family protein) promotes ligand-independent clustering and robust UNC-40 polarization toward UNC-6. Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing UNC-40 clustering. We propose that ligand-independent UNC-40 clustering provides a robust and adaptable mechanism to polarize toward netrin.
    The Journal of Cell Biology 08/2014; 206(5). DOI:10.1083/jcb.201405026 · 9.69 Impact Factor
  • Source
    • "It is not surprising that allowing a parameter to " unfreeze " would lead to more flexible behavior. There are indeed many examples in computational biology where the robustness to input or parameter values, or the range of possible behaviors, are increased by adding dynamic variables (Tomaiuolo et al. 2008; Tsai et al. 2008; Howell et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hodgkin-Huxley (HH) model is the basis for numerous neural models. There are two negative feedback processes in the HH model that regulate rhythmic spiking. The first is an outward current with an activation variable n that has an opposite influence to the excitatory inward current and therefore provides subtractive negative feedback. The other is the inactivation of an inward current with an inactivation variable h that reduces the amount of positive feedback and therefore provides divisive feedback. Rhythmic spiking can be obtained with either negative feedback process, so we ask what is gained by having two feedback processes. We also ask how the different negative feedback processes contribute to spiking. We show that having two negative feedback processes makes the HH model more robust to changes in applied currents and conductance densities than models that possess only one negative feedback variable. We also show that the contributions made by the subtractive and divisive feedback variables are not static, but depend on time scales and conductance values. In particular, they contribute differently to the dynamics in Type I versus Type II neurons.
    Journal of Computational Neuroscience 06/2014; 37(3). DOI:10.1007/s10827-014-0511-y · 2.09 Impact Factor
  • Source
    • "The Ras-like GTPase Rsr1 has long been known to be essential for bud site selection, but our results, as well as the finding presented in several previous studies (Park et al., 2002; Kozminski et al., 2003; Kang et al., 2010), indicate that its role in polarization is more extensive and central to symmetry breaking than previously thought. Although Rsr1 is not strictly required for polarization , especially when actin is intact, in its absence, the established polar cap exhibits drastically reduced spatial and temporal stability , as shown in this and previous studies (Ozbudak et al., 2005; Howell et al., 2012). Previous studies attributed this instability to GAP-mediated negative feedback, and if so, Rsr1 may locally regulate this negative feedback to enhance the stability of the polar cap. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The ability to break symmetry and polarize through self-organization is a fundamental feature of cellular systems. A prevailing theory in yeast posits that symmetry breaking occurs via a positive feedback loop, wherein the adaptor protein Bem1 promotes local activation and accumulation of Cdc42 by directly tethering Cdc42(GTP) with its guanine nucleotide exchange factor (GEF) Cdc24. In this paper, we find that neither Bem1 nor the ability of Bem1 to bind Cdc42(GTP) is required for cell polarization. Instead, Bem1 functions primarily by boosting GEF activity, a role critical for polarization without actin filaments. In the absence of actin-based transport, polarization of Cdc42 is accomplished through Rdi1, the Cdc42 guanine nucleotide dissociation inhibitor. A mathematical model is constructed describing cell polarization as a product of distinct pathways controlling Cdc42 activation and protein localization. The model predicts a nonmonotonic dependence of cell polarization on the concentration of Rdi1 relative to that of Cdc42.
    The Journal of Cell Biology 09/2013; 202(7). DOI:10.1083/jcb.201304180 · 9.69 Impact Factor
Show more