title: RSK2 is a modulator of craniofacial development.
abstract: BACKGROUND
  The RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked dominant genetic disorder causing mental retardation, skeletal growth delays, with craniofacial and digital abnormalities typically associated with this syndrome. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized.
  
  
  RESULTS
  We examined, using X-Ray microtomographic analysis, the variable craniofacial dysmorphism and dental anomalies present in Rsk2 knockout mice, a model of Coffin-Lowry syndrome, as well as in triple Rsk1,2,3 knockout mutants. We report Rsk mutation produces surpernumerary teeth midline/mesial to the first molar. This highly penetrant phenotype recapitulates more ancestral tooth structures lost with evolution. Most likely this leads to a reduction of the maxillary diastema. Abnormalities of molar shape were generally restricted to the mesial part of both upper and lower first molars (M1). Expression analysis of the four Rsk genes (Rsk1, 2, 3 and 4) was performed at various stages of odontogenesis in wild-type (WT) mice. Rsk2 is expressed in the mesenchymal, neural crest-derived compartment, correlating with proliferative areas of the developing teeth. This is consistent with RSK2 functioning in cell cycle control and growth regulation, functions potentially responsible for severe dental phenotypes. To uncover molecular pathways involved in the etiology of these defects, we performed a comparative transcriptomic (DNA microarray) analysis of mandibular wild-type versus Rsk2-/Y molars. We further demonstrated a misregulation of several critical genes, using a Rsk2 shRNA knock-down strategy in molar tooth germs cultured in vitro.
  
  
  CONCLUSIONS
  This study reveals RSK2 regulates craniofacial development including tooth development and patterning via novel transcriptional targets.
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (UMR 7104), Institut National de la Santé et de la Recherche Médicale (U 964), University of Strasbourg, Illkirch, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Laugel-Haushalter
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (UMR 7104), Institut National de la Santé et de la Recherche Médicale (U 964), University of Strasbourg, Illkirch, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Paschaki
authors.affiliation: Team «Evo-Devo of Vertebrate Dentition», Institut de Génomique Fonctionnelle de Lyon, Unité Mixte de Recherche 5242 Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Claude Bernard Lyon 1 University, Lyon, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Marangoni
authors.affiliation: Faculty of Dentistry, University of Strasbourg, Strasbourg France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Pilgram
authors.affiliation: Faculty of Dentistry, University of Strasbourg, Strasbourg France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Langer
authors.affiliation: Faculty of Dentistry, University of Strasbourg, Strasbourg France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Kuntz
authors.affiliation: Faculty of Dentistry, University of Strasbourg, Strasbourg France.
authors.forename: Julie
authors.initials: J
authors.lastname: Demassue
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (UMR 7104), Institut National de la Santé et de la Recherche Médicale (U 964), University of Strasbourg, Illkirch, France ; Faculty of Dentistry, University of Strasbourg, Strasbourg France ; Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Supawich
authors.initials: S
authors.lastname: Morkmued
authors.affiliation: UF6237 Preclinical Imaging Lab, Biophysics and Nuclear Medicine, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France; ICube, CNRS, University of Strasbourg, Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Choquet
authors.affiliation: UF6237 Preclinical Imaging Lab, Biophysics and Nuclear Medicine, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France; ICube, CNRS, University of Strasbourg, Strasbourg, France.
authors.forename: André
authors.initials: A
authors.lastname: Constantinesco
authors.affiliation: Faculty of Dentistry, University of Strasbourg, Strasbourg France ; INSERM U1121, "Biomaterials and Bioengineering", University of Strasbourg, Strasbourg, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Bornert
authors.affiliation: Faculty of Dentistry, University of Strasbourg, Strasbourg France ; Reference Centre for Orodental Manifestations of Rare Diseases, Pôle de Médecine et Chirurgie Bucco-dentaires, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France ; INSERM U1121, "Biomaterials and Bioengineering", University of Strasbourg, Strasbourg, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schmittbuhl
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (UMR 7104), Institut National de la Santé et de la Recherche Médicale (U 964), University of Strasbourg, Illkirch, France.
authors.forename: Solange
authors.initials: S
authors.lastname: Pannetier
authors.affiliation: Team «Evo-Devo of Vertebrate Dentition», Institut de Génomique Fonctionnelle de Lyon, Unité Mixte de Recherche 5242 Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Claude Bernard Lyon 1 University, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Viriot
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (UMR 7104), Institut National de la Santé et de la Recherche Médicale (U 964), University of Strasbourg, Illkirch, France.
authors.forename: André
authors.initials: A
authors.lastname: Hanauer
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (UMR 7104), Institut National de la Santé et de la Recherche Médicale (U 964), University of Strasbourg, Illkirch, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Dollé
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (UMR 7104), Institut National de la Santé et de la Recherche Médicale (U 964), University of Strasbourg, Illkirch, France ; Faculty of Dentistry, University of Strasbourg, Strasbourg France ; Reference Centre for Orodental Manifestations of Rare Diseases, Pôle de Médecine et Chirurgie Bucco-dentaires, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Bloch-Zupan
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D019465:Craniofacial Abnormalities / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006257:Head / Q000254:growth & development*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D009805:Odontogenesis; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014070:Tooth / Q000033:anatomy & histology / Q000254:growth & development
chemical_list: D034741:RNA, Small Interfering; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3