Pulsed feedback defers cellular differentiation.

Environmental signals induce diverse cellular differentiation programs. In certain systems, cells defer differentiation for extended time periods after the signal appears, proliferating through multiple rounds of cell division before committing to a new fate. How can cells set a deferral time much l...

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Autores principales:	Joe H Levine, Michelle E Fontes, Jonathan Dworkin, Michael B Elowitz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0afdea9f2f2345bea2bbdaeebd51936a
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spelling	oai:doaj.org-article:0afdea9f2f2345bea2bbdaeebd51936a2021-11-18T05:36:47ZPulsed feedback defers cellular differentiation.1544-91731545-788510.1371/journal.pbio.1001252https://doaj.org/article/0afdea9f2f2345bea2bbdaeebd51936a2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22303282/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Environmental signals induce diverse cellular differentiation programs. In certain systems, cells defer differentiation for extended time periods after the signal appears, proliferating through multiple rounds of cell division before committing to a new fate. How can cells set a deferral time much longer than the cell cycle? Here we study Bacillus subtilis cells that respond to sudden nutrient limitation with multiple rounds of growth and division before differentiating into spores. A well-characterized genetic circuit controls the concentration and phosphorylation of the master regulator Spo0A, which rises to a critical concentration to initiate sporulation. However, it remains unclear how this circuit enables cells to defer sporulation for multiple cell cycles. Using quantitative time-lapse fluorescence microscopy of Spo0A dynamics in individual cells, we observed pulses of Spo0A phosphorylation at a characteristic cell cycle phase. Pulse amplitudes grew systematically and cell-autonomously over multiple cell cycles leading up to sporulation. This pulse growth required a key positive feedback loop involving the sporulation kinases, without which the deferral of sporulation became ultrasensitive to kinase expression. Thus, deferral is controlled by a pulsed positive feedback loop in which kinase expression is activated by pulses of Spo0A phosphorylation. This pulsed positive feedback architecture provides a more robust mechanism for setting deferral times than constitutive kinase expression. Finally, using mathematical modeling, we show how pulsing and time delays together enable "polyphasic" positive feedback, in which different parts of a feedback loop are active at different times. Polyphasic feedback can enable more accurate tuning of long deferral times. Together, these results suggest that Bacillus subtilis uses a pulsed positive feedback loop to implement a "timer" that operates over timescales much longer than a cell cycle.Joe H LevineMichelle E FontesJonathan DworkinMichael B ElowitzPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 10, Iss 1, p e1001252 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Joe H Levine Michelle E Fontes Jonathan Dworkin Michael B Elowitz Pulsed feedback defers cellular differentiation.
description	Environmental signals induce diverse cellular differentiation programs. In certain systems, cells defer differentiation for extended time periods after the signal appears, proliferating through multiple rounds of cell division before committing to a new fate. How can cells set a deferral time much longer than the cell cycle? Here we study Bacillus subtilis cells that respond to sudden nutrient limitation with multiple rounds of growth and division before differentiating into spores. A well-characterized genetic circuit controls the concentration and phosphorylation of the master regulator Spo0A, which rises to a critical concentration to initiate sporulation. However, it remains unclear how this circuit enables cells to defer sporulation for multiple cell cycles. Using quantitative time-lapse fluorescence microscopy of Spo0A dynamics in individual cells, we observed pulses of Spo0A phosphorylation at a characteristic cell cycle phase. Pulse amplitudes grew systematically and cell-autonomously over multiple cell cycles leading up to sporulation. This pulse growth required a key positive feedback loop involving the sporulation kinases, without which the deferral of sporulation became ultrasensitive to kinase expression. Thus, deferral is controlled by a pulsed positive feedback loop in which kinase expression is activated by pulses of Spo0A phosphorylation. This pulsed positive feedback architecture provides a more robust mechanism for setting deferral times than constitutive kinase expression. Finally, using mathematical modeling, we show how pulsing and time delays together enable "polyphasic" positive feedback, in which different parts of a feedback loop are active at different times. Polyphasic feedback can enable more accurate tuning of long deferral times. Together, these results suggest that Bacillus subtilis uses a pulsed positive feedback loop to implement a "timer" that operates over timescales much longer than a cell cycle.
format	article
author	Joe H Levine Michelle E Fontes Jonathan Dworkin Michael B Elowitz
author_facet	Joe H Levine Michelle E Fontes Jonathan Dworkin Michael B Elowitz
author_sort	Joe H Levine
title	Pulsed feedback defers cellular differentiation.
title_short	Pulsed feedback defers cellular differentiation.
title_full	Pulsed feedback defers cellular differentiation.
title_fullStr	Pulsed feedback defers cellular differentiation.
title_full_unstemmed	Pulsed feedback defers cellular differentiation.
title_sort	pulsed feedback defers cellular differentiation.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/0afdea9f2f2345bea2bbdaeebd51936a
work_keys_str_mv	AT joehlevine pulsedfeedbackdeferscellulardifferentiation AT michelleefontes pulsedfeedbackdeferscellulardifferentiation AT jonathandworkin pulsedfeedbackdeferscellulardifferentiation AT michaelbelowitz pulsedfeedbackdeferscellulardifferentiation
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Pulsed feedback defers cellular differentiation.

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