title: Fast synchronization of ultradian oscillators controlled by delta-notch signaling with cis-inhibition.
abstract: While it is known that a large fraction of vertebrate genes are under the control of a gene regulatory network (GRN) forming a clock with circadian periodicity, shorter period oscillatory genes like the Hairy-enhancer-of split (Hes) genes are discussed mostly in connection with the embryonic process of somitogenesis. They form the core of the somitogenesis-clock, which orchestrates the periodic separation of somites from the presomitic mesoderm (PSM). The formation of sharp boundaries between the blocks of many cells works only when the oscillators in the cells forming the boundary are synchronized. It has been shown experimentally that Delta-Notch (D/N) signaling is responsible for this synchronization. This process has to happen rather fast as a cell experiences at most five oscillations from its 'birth' to its incorporation into a somite. Computer simulations describing synchronized oscillators with classical modes of D/N-interaction have difficulties to achieve synchronization in an appropriate time. One approach to solving this problem of modeling fast synchronization in the PSM was the consideration of cell movements. Here we show that fast synchronization of Hes-type oscillators can be achieved without cell movements by including D/N cis-inhibition, wherein the mutual interaction of DELTA and NOTCH in the same cell leads to a titration of ligand against receptor so that only one sort of molecule prevails. Consequently, the symmetry between sender and receiver is partially broken and one cell becomes preferentially sender or receiver at a given moment, which leads to faster entrainment of oscillators. Although not yet confirmed by experiment, the proposed mechanism of enhanced synchronization of mesenchymal cells in the PSM would be a new distinct developmental mechanism employing D/N cis-inhibition. Consequently, the way in which Delta-Notch signaling was modeled so far should be carefully reconsidered.
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Hendrik B
authors.initials: HB
authors.lastname: Tiedemann
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Elida
authors.initials: E
authors.lastname: Schneltzer
authors.affiliation: Kinesis Pharma BV, Breda, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeiser
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Technische Universität München, Center of Life and Food Sciences Weihenstephan, Chair of Developmental Genetics, Freising, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Technische Universität München, Center of Life and Food Sciences Weihenstephan, Chair of Experimental Genetics, Freising, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Gerhard K H
authors.initials: GK
authors.lastname: Przemeck
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Technische Universität München, Center of Life and Food Sciences Weihenstephan, Chair of Experimental Genetics, Freising, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001683:Biological Clocks / Q000235:genetics*; D019295:Computational Biology; D053263:Gene Regulatory Networks / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D012333:RNA, Messenger; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; C430525:Hes7 protein, mouse; C497762:Notch1 protein, mouse; C064045:delta protein