title: microRNA input into a neural ultradian oscillator controls emergence and timing of alternative cell states.
abstract: Progenitor maintenance, timed differentiation and the potential to enter quiescence are three fundamental processes that underlie the development of any organ system. In the nervous system, progenitor cells show short-period oscillations in the expression of the transcriptional repressor Hes1, while neurons and quiescent progenitors show stable low and high levels of Hes1, respectively. Here we use experimental data to develop a mathematical model of the double-negative interaction between Hes1 and a microRNA, miR-9, with the aim of understanding how cells transition from one state to another. We show that the input of miR-9 into the Hes1 oscillator tunes its oscillatory dynamics, and endows the system with bistability and the ability to measure time to differentiation. Our results suggest that a relatively simple and widespread network of cross-repressive interactions provides a unifying framework for progenitor maintenance, the timing of differentiation and the emergence of alternative cell states.
authors.affiliation: 1] Faculty of Life Sciences, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK [2] Present address: College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, Devon EX4 4QF, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Goodfellow
authors.affiliation: Faculty of Life Sciences, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Phillips
authors.affiliation: Faculty of Life Sciences, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Cerys
authors.initials: C
authors.lastname: Manning
authors.affiliation: Theoretical Physics, School of Physics and Astronomy, The University of Manchester, Manchester M13 9PL, UK.
authors.forename: Tobias
authors.initials: T
authors.lastname: Galla
authors.affiliation: Faculty of Life Sciences, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Nancy
authors.initials: N
authors.lastname: Papalopulu
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008962:Models, Theoretical; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D049490:Systems Biology; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C551804:MIRN9 microRNA, mouse