title: Designing synthetic regulatory networks capable of self-organizing cell polarization.
abstract: How cells form global, self-organized structures using genetically encoded molecular rules remains elusive. Here, we take a synthetic biology approach to investigate the design principles governing cell polarization. First, using a coarse-grained computational model, we searched for all possible simple networks that can achieve polarization. All solutions contained one of three minimal motifs: positive feedback, mutual inhibition, or inhibitor with positive feedback. These minimal motifs alone could achieve polarization under limited conditions; circuits that combined two or more of these motifs were significantly more robust. With these design principles as a blueprint, we experimentally constructed artificial polarization networks in yeast, using a toolkit of chimeric signaling proteins that spatially direct the synthesis and degradation of phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)). Circuits with combinatorial motifs yielded clear foci of synthetic PIP(3) that can persist for nearly an hour. Thus, by harnessing localization-regulated signaling molecules, we can engineer simple molecular circuits that reliably execute spatial self-organized programs.
authors.affiliation: Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Angela H
authors.initials: AH
authors.lastname: Chau
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Walter
authors.forename: Jaline
authors.initials: J
authors.lastname: Gerardin
authors.forename: Chao
authors.initials: C
authors.lastname: Tang
authors.forename: Wendell A
authors.initials: WA
authors.lastname: Lim
mesh_terms: D000465:Algorithms; D016764:Cell Polarity; D003600:Cytosol / Q000378:metabolism; D025461:Feedback, Physiological; D008954:Models, Biological; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology*; D058615:Synthetic Biology
chemical_list: D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate