title: Toward pathogenesis of Apert cleft palate: FGF, FGFR, and TGF beta genes are differentially expressed in sequential stages of human palatal shelf fusion.
abstract: OBJECTIVE
  Critical cellular events at the palatal medial edge epithelium (MEE) occur in unperturbed mammalian palatogenesis, the molecular control of which involves a number of growth factors including transforming growth factor beta 3 (TGF beta 3). Apert syndrome is a monogenic human disorder in which cleft palate has been significantly correlated to the fibroblast growth factor receptor (FGFR) 2-Ser252Trp mutation. We report the relative expression of these genes in human palatogenesis.
  
  
  METHODS
  The expression of the IgIIIa/b and IgIIIa/c transcript isoforms of FGFR2 and the proteins FGFR1, FGFR2, and FGFR3 was studied in situ throughout the temporospatial sequence of human palatal shelf fusion and correlated with the expression of TGF beta 3. In addition, the immunolocalization of the ligand FGFs 2, 4, and 7 was undertaken together with the intracellular transcription factor STAT1, which is activated by FGFR signaling.
  
  
  RESULTS
  FGFRs are differentially expressed in the mesenchyme and epithelia of fusing palatal shelves, in domains overlapping those of their ligands FGF4 and FGF2 but not FGF7. Coexpression is seen with TGF beta 3, which is implicated in MEE dynamics and FGF and FGFR upregulation, and STAT1, an intracellular transcription factor that mediates apoptosis.
  
  
  CONCLUSIONS
  The coregulation of molecules of the FGFR signaling pathway with TGF beta 3 throughout the stages of human palatal fusion suggests their controlling influence on apoptosis and epitheliomesenchymal transdifferentiation at the MEE. Experimental evidence links FGFR2-IgIIIa/b loss of function with palatal clefting, and these correlated data suggest a unique pathological mechanism for Apert cleft palate.
authors.affiliation: Craniofacial Centre, Great Ormond Street Hospital for Children, London, England, United Kingdom. j.britto@btinternet.com
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Britto
authors.forename: Robert D
authors.initials: RD
authors.lastname: Evans
authors.forename: Richard D
authors.initials: RD
authors.lastname: Hayward
authors.forename: Barry M
authors.initials: BM
authors.lastname: Jones
mesh_terms: D000168:Acrocephalosyndactylia / Q000209:etiology* / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D002972:Cleft Palate / Q000209:etiology* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004848:Epithelium / Q000196:embryology; D005091:Exons / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D015603:Keratinocytes / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010159:Palate / Q000196:embryology*; D020033:Protein Isoforms / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D050794:STAT1 Transcription Factor; D012694:Serine / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053782:Transforming Growth Factor beta3; D014364:Tryptophan / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C496453:FGF7 protein, human; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3; C112971:fibroblast growth factor 14; D016222:Fibroblast Growth Factor 2; D051523:Fibroblast Growth Factor 7; D012694:Serine; D005346:Fibroblast Growth Factors; D014364:Tryptophan