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

Goodfellow M, Phillips NE, Manning C, Galla T, Papalopulu N - Nat Commun (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

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The model can display bistability, sustained oscillations, stable high or low levels of Hes1 depending upon its parameterization.Local bifurcations are shown for changes in the miR-9 degradation rate, μr, the strength of repression of miR-9 production by Hes1, p1 and the shape of repression of miR-9 production by Hes1, n1. The presence of Hopf and fold bifurcations are indicated by blue and red solid lines, respectively. Fold bifurcations lead to the creation or elimination of a pair of fixed points. Blue regions, therefore, indicate the presence of oscillations, while red regions indicate bistability. White regions represent the case of a single steady state with either high or low Hes1 levels (as indicated by the annotation). (a) n1=1. (b) n1=5. Other parameters are p0=390, τ=29 min, bl=ln(2)/20 min−1, bu=ln(2)/35 min−1, n0=m0=m1=5, r0=100, r1=300, μp=22 min.
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f7: The model can display bistability, sustained oscillations, stable high or low levels of Hes1 depending upon its parameterization.Local bifurcations are shown for changes in the miR-9 degradation rate, μr, the strength of repression of miR-9 production by Hes1, p1 and the shape of repression of miR-9 production by Hes1, n1. The presence of Hopf and fold bifurcations are indicated by blue and red solid lines, respectively. Fold bifurcations lead to the creation or elimination of a pair of fixed points. Blue regions, therefore, indicate the presence of oscillations, while red regions indicate bistability. White regions represent the case of a single steady state with either high or low Hes1 levels (as indicated by the annotation). (a) n1=1. (b) n1=5. Other parameters are p0=390, τ=29 min, bl=ln(2)/20 min−1, bu=ln(2)/35 min−1, n0=m0=m1=5, r0=100, r1=300, μp=22 min.

Mentions: A comprehensive analysis of the presence of Hopf and fold bifurcations in the full system and its resulting dynamics is shown in Fig. 7 and Supplementary Fig. 5. Hopf and fold bifurcations exist for a range of n1, p1 and μr values, although their relative position in parameter space is dependent on the choice of n1.


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

Goodfellow M, Phillips NE, Manning C, Galla T, Papalopulu N - Nat Commun (2014)

The model can display bistability, sustained oscillations, stable high or low levels of Hes1 depending upon its parameterization.Local bifurcations are shown for changes in the miR-9 degradation rate, μr, the strength of repression of miR-9 production by Hes1, p1 and the shape of repression of miR-9 production by Hes1, n1. The presence of Hopf and fold bifurcations are indicated by blue and red solid lines, respectively. Fold bifurcations lead to the creation or elimination of a pair of fixed points. Blue regions, therefore, indicate the presence of oscillations, while red regions indicate bistability. White regions represent the case of a single steady state with either high or low Hes1 levels (as indicated by the annotation). (a) n1=1. (b) n1=5. Other parameters are p0=390, τ=29 min, bl=ln(2)/20 min−1, bu=ln(2)/35 min−1, n0=m0=m1=5, r0=100, r1=300, μp=22 min.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3959193&req=5

f7: The model can display bistability, sustained oscillations, stable high or low levels of Hes1 depending upon its parameterization.Local bifurcations are shown for changes in the miR-9 degradation rate, μr, the strength of repression of miR-9 production by Hes1, p1 and the shape of repression of miR-9 production by Hes1, n1. The presence of Hopf and fold bifurcations are indicated by blue and red solid lines, respectively. Fold bifurcations lead to the creation or elimination of a pair of fixed points. Blue regions, therefore, indicate the presence of oscillations, while red regions indicate bistability. White regions represent the case of a single steady state with either high or low Hes1 levels (as indicated by the annotation). (a) n1=1. (b) n1=5. Other parameters are p0=390, τ=29 min, bl=ln(2)/20 min−1, bu=ln(2)/35 min−1, n0=m0=m1=5, r0=100, r1=300, μp=22 min.
Mentions: A comprehensive analysis of the presence of Hopf and fold bifurcations in the full system and its resulting dynamics is shown in Fig. 7 and Supplementary Fig. 5. Hopf and fold bifurcations exist for a range of n1, p1 and μr values, although their relative position in parameter space is dependent on the choice of n1.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH