title: Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain.
abstract: Morphogen gradients induce sharply defined domains of gene expression in a concentration-dependent manner, yet how cells interpret these signals in the face of spatial and temporal noise remains unclear. Using fluorescence lifetime imaging microscopy (FLIM) and phasor analysis to measure endogenous retinoic acid (RA) directly in vivo, we have investigated the amplitude of noise in RA signaling, and how modulation of this noise affects patterning of hindbrain segments (rhombomeres) in the zebrafish embryo. We demonstrate that RA forms a noisy gradient during critical stages of hindbrain patterning and that cells use distinct intracellular binding proteins to attenuate noise in RA levels. Increasing noise disrupts sharpening of rhombomere boundaries and proper patterning of the hindbrain. These findings reveal novel cellular mechanisms of noise regulation, which are likely to play important roles in other aspects of physiology and disease.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States.|Center for Complex Biological Systems, University of California, Irvine, Irvine, United States.|Department of Interdisciplinary Engineering, Wentworth Institute of Technology, Boston, United States.
authors.forename: Julian
authors.initials: J
authors.lastname: Sosnik
authors.affiliation: Center for Complex Biological Systems, University of California, Irvine, Irvine, United States.|Department of Mathematics, University of California, Irvine, Irvine, United States.
authors.forename: Likun
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Center for Complex Biological Systems, University of California, Irvine, Irvine, United States.|Department of Mathematics, University of California, Irvine, Irvine, United States.
authors.forename: Christopher V
authors.identifier: http://orcid.org/0000-0001-5850-0663
authors.initials: CV
authors.lastname: Rackauckas
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States.|Center for Complex Biological Systems, University of California, Irvine, Irvine, United States.|Department of Biomedical Engineering, University of California, Irvine, Irvine, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Digman
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States.|Center for Complex Biological Systems, University of California, Irvine, Irvine, United States.|Department of Biomedical Engineering, University of California, Irvine, Irvine, United States.
authors.forename: Enrico
authors.initials: E
authors.lastname: Gratton
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States.|Center for Complex Biological Systems, University of California, Irvine, Irvine, United States.|Department of Mathematics, University of California, Irvine, Irvine, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Nie
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States.|Center for Complex Biological Systems, University of California, Irvine, Irvine, United States.
authors.forename: Thomas F
authors.identifier: http://orcid.org/0000-0003-1798-8695
authors.initials: TF
authors.lastname: Schilling
mesh_terms: D000818:Animals; D018507:Gene Expression Regulation, Developmental; D012249:Rhombencephalon / Q000196:embryology*; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*
chemical_list: D014212:Tretinoin
keywords: Danio rerio; computational biology; developmental biology; hindbrain; morphogen; noise; retinoic acid; rhombomere; stem cells; systems biology; zebrafish