Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
| Autor: | Federico Coluccio Leskow, Xin Geng, Douglas J. Epstein, Xue Li, Maximilian Muenke, Kenia B. El-Jaick, Anastasia K. Yocum, Christèle Dubourg, Erich Roessler, Guillermo Oliver, Yongsu Jeong |
|---|---|
| Přispěvatelé: | University of Pennsylvania School of Veterinary Medicine, Cancer Genetics Branch, National Institute of Health (NIH)-National Human Genome Research Institute (NHGRI), Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Service de biologie moléculaire, Hôpital Pontchaillou, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Surgery/Urology, Harvard Medical School [Boston] (HMS)-Boston Children's Hospital, Department of Genetics, St Jude Children's Research Hospital, University of Pennsylvania School of Medicine, University of Pennsylvania [Philadelphia], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), De Villemeur, Hervé |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
[SDV.GEN] Life Sciences [q-bio]/Genetics
MESH: Base Sequence 0302 clinical medicine Holoprosencephaly MESH: Eye Proteins Transcription (biology) Mouse development MESH: Animals MESH: Nerve Tissue Proteins Sonic hedgehog [SDV.BDD]Life Sciences [q-bio]/Development Biology 0303 health sciences MESH: COS Cells embryonic structures forebrain enhancer Haploinsufficiency MESH: Holoprosencephaly Six CIENCIAS NATURALES Y EXACTAS Genetically modified mouse animal structures MESH: Mutation MESH: Trans-Activators [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Ciencias Biológicas 03 medical and health sciences Biología Celular Microbiología [SDV.BDD] Life Sciences [q-bio]/Development Biology MESH: Homeodomain Proteins Genetics medicine MESH: Protein Binding Enhancer [SDV.BC] Life Sciences [q-bio]/Cellular Biology MESH: Mice 030304 developmental biology [SDV.GEN]Life Sciences [q-bio]/Genetics MESH: Molecular Sequence Data MESH: Humans MESH: Hedgehog Proteins medicine.disease Molecular biology MESH: Cercopithecus aethiops MESH: Hypothalamus Forebrain biology.protein Homeobox sense organs 030217 neurology & neurosurgery |
| Zdroj: | Nature Genetics Nature Genetics, 2008, 40 (11), pp.1348-53. ⟨10.1038/ng.230⟩ Nature Genetics, Nature Publishing Group, 2008, 40 (11), pp.1348-53. ⟨10.1038/ng.230⟩ |
| ISSN: | 1061-4036 1546-1718 |
| DOI: | 10.1038/ng.230⟩ |
| Popis: | In humans, SHH haploinsufficiency results in holoprosencephaly (HPE), a defect in anterior midline formation. Despite the importance of maintaining SHH transcript levels above a critical threshold, we know little about the upstream regulators of SHH expression in the forebrain. Here we describe a rare nucleotide variant located 460 kb upstream of SHH in an individual with HPE that resulted in the loss of Shh brain enhancer-2 (SBE2) activity in the hypothalamus of transgenic mouse embryos. Using a DNA affinity-capture assay, we screened the SBE2 sequence for DNA-binding proteins and identified members of the Six3 and Six6 homeodomain family as candidate regulators of Shh transcription. Six3 showed reduced binding affinity for the mutant compared to the wild-type SBE2 sequence. Moreover, Six3 with HPE-causing alterations failed to bind and activate SBE2. These data suggest a direct link between Six3 and Shh regulation during normal forebrain development and in the pathogenesis of HPE. Fil: Jeong, Yongsu. University of Pennsylvania; Estados Unidos Fil: Coluccio Leskow, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pennsylvania; Estados Unidos Fil: El Jaick, Kenia. National Institutes of Health; Estados Unidos Fil: Roessler, Erich. National Institutes of Health; Estados Unidos Fil: Muenke, Maximilian. National Institutes of Health; Estados Unidos Fil: Yocum, Anastasia. University of Pennsylvania; Estados Unidos Fil: Dubourg, Christele. Universite de Rennes I; Francia Fil: Li, Xue. Children’s Hospital of Boston; Estados Unidos Fil: Geng, Xin. St. Jude Children’s Research Hospital; Estados Unidos Fil: Oliver, Guillermo. St. Jude Children’s Research Hospital; Estados Unidos Fil: Epstein, Douglas J.. University of Pennsylvania; Estados Unidos |
| Databáze: | OpenAIRE |
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