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      Evolution of antero‐posterior patterning of the limb: Insights from the chick

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          Summary

          The developing limbs of chicken embryos have served as pioneering models for understanding pattern formation for over a century. The ease with which chick wing and leg buds can be experimentally manipulated, while the embryo is still in the egg, has resulted in the discovery of important developmental organisers, and subsequently, the signals that they produce. Sonic hedgehog (Shh) is produced by mesenchyme cells of the polarizing region at the posterior margin of the limb bud and specifies positional values across the antero‐posterior axis (the axis running from the thumb to the little finger). Detailed experimental embryology has revealed the fundamental parameters required to specify antero‐posterior positional values in response to Shh signaling in chick wing and leg buds. In this review, the evolution of the avian wing and leg will be discussed in the broad context of tetrapod paleontology, and more specifically, ancestral theropod dinosaur paleontology. How the parameters that dictate antero‐posterior patterning could have been modulated to produce the avian wing and leg digit patterns will be considered. Finally, broader speculations will be made regarding what the antero‐posterior patterning of chick limbs can tell us about the evolution of other digit patterns, including those that were found in the limbs of the earliest tetrapods.

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          Primary Cilia and Mammalian Hedgehog Signaling.

          It has been a decade since it was discovered that primary cilia have an essential role in Hedgehog (Hh) signaling in mammals. This discovery came from screens in the mouse that identified a set of genes that are required for both normal Hh signaling and for the formation of primary cilia. Since then, dozens of mouse mutations have been identified that disrupt cilia in a variety of ways and have complex effects on Hedgehog signaling. Here, we summarize the genetic and developmental studies used to deduce how Hedgehog signal transduction is linked to cilia and the complex effects that perturbation of cilia structure can have on Hh signaling. We conclude by describing the current status of our understanding of the cell-type-specific regulation of ciliogenesis and how that determines the ability of cells to respond to Hedgehog ligands.
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            Sonic hedgehog mediates the polarizing activity of the ZPA.

            The zone of polarizing activity (ZPA) is a region at the posterior margin of the limb bud that induces mirror-image duplications when grafted to the anterior of a second limb. We have isolated a vertebrate gene, Sonic hedgehog, related to the Drosophila segment polarity gene hedgehog, which is expressed specifically in the ZPA and in other regions of the embryo, that is capable of polarizing limbs in grafting experiments. Retinoic acid, which can convert anterior limb bud tissue into tissue with polarizing activity, concomitantly induces Sonic hedgehog expression in the anterior limb bud. Implanting cells that express Sonic hedgehog into anterior limb buds is sufficient to cause ZPA-like limb duplications. Like the ZPA, Sonic hedgehog expression leads to the activation of Hox genes. Sonic hedgehog thus appears to function as the signal for antero-posterior patterning in the limb.
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              Modeling digits. Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.

              During limb development, digits emerge from the undifferentiated mesenchymal tissue that constitutes the limb bud. It has been proposed that this process is controlled by a self-organizing Turing mechanism, whereby diffusible molecules interact to produce a periodic pattern of digital and interdigital fates. However, the identities of the molecules remain unknown. By combining experiments and modeling, we reveal evidence that a Turing network implemented by Bmp, Sox9, and Wnt drives digit specification. We develop a realistic two-dimensional simulation of digit patterning and show that this network, when modulated by morphogen gradients, recapitulates the expression patterns of Sox9 in the wild type and in perturbation experiments. Our systems biology approach reveals how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation.
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                Author and article information

                Contributors
                m.towers@sheffield.ac.uk
                Journal
                Genesis
                Genesis
                10.1002/(ISSN)1526-968X
                DVG
                Genesis (New York, N.y. : 2000)
                John Wiley and Sons Inc. (Hoboken )
                1526-954X
                1526-968X
                22 July 2017
                January 2018
                : 56
                : 1 , Limb Development and Evolution ( doiID: 10.1002/dvg.v56.1 )
                : e23047
                Affiliations
                [ 1 ] Department of Biomedical Science The Bateson Centre, University of Sheffield Western Bank Sheffield S10 2TN United Kingdom
                Author notes
                [*] [* ] Correspondence Matthew Towers, Department of Biomedical Science, The Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, United Kingdom. Email: m.towers@ 123456sheffield.ac.uk
                Author information
                http://orcid.org/0000-0003-2189-4536
                Article
                DVG23047
                10.1002/dvg.23047
                5811799
                28734068
                fd5a822d-7dcf-4dcd-ba5f-465856067c5d
                © 2017 The Authors The Journal of Genetics and Development Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 05 April 2017
                : 23 June 2017
                : 27 June 2017
                Page count
                Figures: 6, Tables: 0, Pages: 15, Words: 13021
                Funding
                Funded by: Wellcome Trust
                Award ID: 202756/Z/16/Z
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                dvg23047
                January 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:14.02.2018

                Molecular biology
                avian,chick,digits,dinosaur,limb,positional information,self organization,shh,theropod,tetrapod
                Molecular biology
                avian, chick, digits, dinosaur, limb, positional information, self organization, shh, theropod, tetrapod

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