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      Morphogen rules: design principles of gradient-mediated embryo patterning

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          Abstract

          The Drosophila blastoderm and the vertebrate neural tube are archetypal examples of morphogen-patterned tissues that create precise spatial patterns of different cell types. In both tissues, pattern formation is dependent on molecular gradients that emanate from opposite poles. Despite distinct evolutionary origins and differences in time scales, cell biology and molecular players, both tissues exhibit striking similarities in the regulatory systems that establish gene expression patterns that foreshadow the arrangement of cell types. First, signaling gradients establish initial conditions that polarize the tissue, but there is no strict correspondence between specific morphogen thresholds and boundary positions. Second, gradients initiate transcriptional networks that integrate broadly distributed activators and localized repressors to generate patterns of gene expression. Third, the correct positioning of boundaries depends on the temporal and spatial dynamics of the transcriptional networks. These similarities reveal design principles that are likely to be broadly applicable to morphogen-patterned tissues.

          Abstract

          Summary: This Review discusses similarities between the mechanisms patterning the Drosophila blastoderm and the vertebrate neural tube, suggesting a set of principles for morphogen-patterned tissues.

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          Most cited references118

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          In vivo dynamics of RNA polymerase II transcription.

          We imaged transcription in living cells using a locus-specific reporter system, which allowed precise, single-cell kinetic measurements of promoter binding, initiation and elongation. Photobleaching of fluorescent RNA polymerase II revealed several kinetically distinct populations of the enzyme interacting with a specific gene. Photobleaching and photoactivation of fluorescent MS2 proteins used to label nascent messenger RNAs provided sensitive elongation measurements. A mechanistic kinetic model that fits our data was validated using specific inhibitors. Polymerases elongated at 4.3 kilobases min(-1), much faster than previously documented, and entered a paused state for unexpectedly long times. Transcription onset was inefficient, with only 1% of polymerase-gene interactions leading to completion of an mRNA. Our systems approach, quantifying both polymerase and mRNA kinetics on a defined DNA template in vivo with high temporal resolution, opens new avenues for studying regulation of transcriptional processes in vivo.
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            Morphogen gradients: from generation to interpretation.

            Morphogens are long-range signaling molecules that pattern developing tissues in a concentration-dependent manner. The graded activity of morphogens within tissues exposes cells to different signal levels and leads to region-specific transcriptional responses and cell fates. In its simplest incarnation, a morphogen signal forms a gradient by diffusion from a local source and clearance in surrounding tissues. Responding cells often transduce morphogen levels in a linear fashion, which results in the graded activation of transcriptional effectors. The concentration-dependent expression of morphogen target genes is achieved by their different binding affinities for transcriptional effectors as well as inputs from other transcriptional regulators. Morphogen distribution and interpretation are the result of complex interactions between the morphogen and responding tissues. The response to a morphogen is dependent not simply on morphogen concentration but also on the duration of morphogen exposure and the state of the target cells. In this review, we describe the morphogen concept and discuss the mechanisms that underlie the generation, modulation, and interpretation of morphogen gradients.
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              The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner.

              The bicoid (bcd) protein in a Drosophila embryo is derived from an anteriorly localized mRNA and comes to be distributed in an exponential concentration gradient along the anteroposterior axis. To determine whether the levels of bcd protein are directly related to certain cell fates, we manipulated the density and distribution of bcd mRNA by genetic means, measured the resultant alterations in height and shape of the bcd protein gradient, and correlated the gradient with the fate map of the respective embryos. Increases or decreases in bcd protein levels in a given region of the embryo cause a corresponding posterior or anterior shift of anterior anlagen in the embryo. The bcd protein thus has the properties of a morphogen that autonomously determines positions in the anterior half of the embryo.
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                Author and article information

                Journal
                Development
                Development
                DEV
                develop
                Development (Cambridge, England)
                The Company of Biologists
                0950-1991
                1477-9129
                1 December 2015
                1 December 2016
                : 142
                : 23
                : 3996-4009
                Affiliations
                [1 ]The Francis Crick Institute , Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, UK
                [2 ]Department of Biology, New York University , 100 Washington Square East, New York, NY 10003, USA
                Author notes
                [* ]Authors for correspondence ( james.briscoe@ 123456crick.ac.uk ; sjs1@ 123456nyu.edu )
                Article
                DEV129452
                10.1242/dev.129452
                4712844
                26628090
                6d9ffd20-15d2-4278-bd0c-4010a3bef612
                © 2015. Published by The Company of Biologists Ltd

                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.

                History
                Categories
                Review

                Developmental biology
                bicoid,drosophila blastoderm,gene regulatory network,morphogen interpretation,sonic hedgehog,vertebrate neural tube

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