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A theoretical framework for the regulation of Shh morphogen-controlled gene expression.

Cohen, M; Page, KM; Perez-Carrasco, R; Barnes, CP; Briscoe, J; (2014) A theoretical framework for the regulation of Shh morphogen-controlled gene expression. Development , 141 (20) 3868 - 3878. 10.1242/dev.112573. Green open access

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Abstract

How morphogen gradients govern the pattern of gene expression in developing tissues is not well understood. Here, we describe a statistical thermodynamic model of gene regulation that combines the activity of a morphogen with the transcriptional network it controls. Using Sonic hedgehog (Shh) patterning of the ventral neural tube as an example, we show that the framework can be used together with the principled parameter selection technique of approximate Bayesian computation to obtain a dynamical model that accurately predicts tissue patterning. The analysis indicates that, for each target gene regulated by Gli, which is the transcriptional effector of Shh signalling, there is a neutral point in the gradient, either side of which altering the Gli binding affinity has opposite effects on gene expression. This explains recent counterintuitive experimental observations. The approach is broadly applicable and provides a unifying framework to explain the temporospatial pattern of morphogen-regulated gene expression.

Type: Article
Title: A theoretical framework for the regulation of Shh morphogen-controlled gene expression.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/dev.112573
Publisher version: http://dx.doi.org/10.1242/dev.112573
Language: English
Additional information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: Approximate Bayesian computation, Enhancer, Gene regulation, Gli, Mathematical modelling, Morphogen patterning, Shh, Transcriptional networks
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Mathematics
URI: http://discovery.ucl.ac.uk/id/eprint/1452132
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