microRNA input into a neural ultradian oscillator controls emergence and timing of alternative cell states

Marc Goodfellow, Nicholas E. Phillips, Cerys Manning, Tobias Galla and Nancy Papalopulu ()
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Marc Goodfellow: Faculty of Life Sciences, Michael Smith Building, The University of Manchester
Nicholas E. Phillips: Faculty of Life Sciences, Michael Smith Building, The University of Manchester
Cerys Manning: Faculty of Life Sciences, Michael Smith Building, The University of Manchester
Tobias Galla: Theoretical Physics, School of Physics and Astronomy, The University of Manchester
Nancy Papalopulu: Faculty of Life Sciences, Michael Smith Building, The University of Manchester

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4399

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