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      Sonic Hedgehog Signaling Is Required for Cyp26 Expression during Embryonic Development

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          Abstract

          Deciphering how signaling pathways interact during development is necessary for understanding the etiopathogenesis of congenital malformations and disease. In several embryonic structures, components of the Hedgehog and retinoic acid pathways, two potent players in development and disease are expressed and operate in the same or adjacent tissues and cells. Yet whether and, if so, how these pathways interact during organogenesis is, to a large extent, unclear. Using genetic and experimental approaches in the mouse, we show that during development of ontogenetically different organs, including the tail, genital tubercle, and secondary palate, Sonic hedgehog (SHH) loss-of-function causes anomalies phenocopying those induced by enhanced retinoic acid signaling and that SHH is required to prevent supraphysiological activation of retinoic signaling through maintenance and reinforcement of expression of the Cyp26 genes. Furthermore, in other tissues and organs, disruptions of the Hedgehog or the retinoic acid pathways during development generate similar phenotypes. These findings reveal that rigidly calibrated Hedgehog and retinoic acid activities are required for normal organogenesis and tissue patterning.

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          Most cited references146

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          Patched1 regulates hedgehog signaling at the primary cilium.

          Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.
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            Small molecule modulation of Smoothened activity.

            Smoothened (Smo), a distant relative of G protein-coupled receptors, mediates Hedgehog (Hh) signaling during embryonic development and can initiate or transmit ligand-independent pathway activation in tumorigenesis. Although the cellular mechanisms that regulate Smo function remain unclear, the direct inhibition of Smo by cyclopamine, a plant-derived steroidal alkaloid, suggests that endogenous small molecules may be involved. Here we demonstrate that SAG, a chlorobenzothiophene-containing Hh pathway agonist, binds to the Smo heptahelical bundle in a manner that antagonizes cyclopamine action. In addition, we have identified four small molecules that directly inhibit Smo activity but are structurally distinct from cyclopamine. Functional and biochemical studies of these compounds provide evidence for the small molecule modulation of Smo through multiple mechanisms and yield insights into the physiological regulation of Smo activity. The mechanistic differences between the Smo antagonists may be useful in the therapeutic manipulation of Hh signaling.
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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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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                08 May 2019
                May 2019
                : 20
                : 9
                : 2275
                Affiliations
                [1 ]Department of Oral Biochemistry, Sahlgrenska Academy at the University of Gothenburg, SE-40530 Göteborg, Sweden; maha.el.shahawy@ 123456odontologi.gu.se (M.E.S.); claes-goran.reibring@ 123456gu.se (C.-G.R.); kristina.hallberg@ 123456odontologi.gu.se (K.H.); linde@ 123456odontologi.gu.se (A.L.)
                [2 ]Department of Oral Biology, Minia University, Minia 51161, Egypt
                [3 ]Program in Craniofacial Biology and Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, USA; cynthianeben@ 123456gmail.com (C.L.N.); Pauline.Marangoni@ 123456ucsf.edu (P.M.); Ophir.Klein@ 123456ucsf.edu (O.D.K.)
                [4 ]Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA; bharfe@ 123456UFL.EDU
                [5 ]Department of Pediatrics and Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA
                Author notes
                [* ]Correspondence: amel@ 123456odontologi.gu.se ; Tel.: +46-31-7863392
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-7122-1191
                https://orcid.org/0000-0002-0519-9157
                https://orcid.org/0000-0002-3780-7452
                https://orcid.org/0000-0001-6489-1269
                Article
                ijms-20-02275
                10.3390/ijms20092275
                6540044
                31072004
                b35f2a88-7f15-4ddb-a123-074f816b7259
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 April 2019
                : 03 May 2019
                Categories
                Article

                Molecular biology
                cyp26 enzymes,congenital anomalies,cre/loxp,hedgehog signaling,mouse models,retinoic acid,smoothened,sonic hedgehog

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