RSK2 is a modulator of craniofacial development

PLoS One. 2014 Jan 8;9(1):e84343. doi: 10.1371/journal.pone.0084343. eCollection 2014.


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.

Methodology/principal findings: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / enzymology
  • Abnormalities, Multiple / pathology
  • Abnormalities, Multiple / physiopathology
  • Animals
  • Craniofacial Abnormalities / enzymology*
  • Craniofacial Abnormalities / pathology
  • Craniofacial Abnormalities / physiopathology
  • Enzyme Activation
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Head / growth & development*
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Odontogenesis
  • Phenotype
  • RNA, Small Interfering / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / deficiency
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Tooth / anatomy & histology
  • Tooth / growth & development


  • RNA, Small Interfering
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3

Grant support

This work was supported by grants (to AB-Z) from the University of Strasbourg, the Hôpitaux Universitaires de Strasbourg (API, 2009-2012, “Development of the oral cavity: from gene to clinical phenotype in Human”), IFRO (Institut Français pour la Recherche Odontologique), by institutional funds from the Centre National de la Recherche Scientifique (CNRS) and Institut National de la Santé et de la Recherche Médicale (INSERM). This project, A27 “Orodental manifestations of rare diseases”, selected by the Offensive Sciences of the Trinational Metropolitan Area Upper Rhine (TMR), is co-financed by the European Regional Development Fund (ERDF) of the European Union, in the framework of the INTERREG IV Upper Rhine programme. VL-H was the recipient of a PhD fellowship from the Ministère Français de la Recherche. MP was supported by a grant from the Agence Nationale de la Recherche (to PD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.