title: Effects of FGFR Signaling on Cell Proliferation and Differentiation of Apert Dental Cells.
abstract: The Apert syndrome is a rare congenital disorder most often arising from S252W or P253R mutations in fibroblast growth factor receptor (FGFR2). Numerous studies have focused on the regulatory role of Apert FGFR2 signaling in bone formation, whereas its functional role in tooth development is largely unknown. To investigate the role of FGFR signaling in cell proliferation and odontogenic differentiation of human dental cells in vitro, we isolated dental pulp and enamel organ epithelia (EOE) tissues from an Apert patient carrying the S252W FGFR2 mutation. Apert primary pulp and EOE cells were established and shown to exhibit normal morphology and express alkaline phosphatase under differentiation conditions. Similar to control cells, Apert dental pulp and EOE cells expressed all FGFRs, with highest levels of FGFR1 followed by FGFR2 and low levels of FGFR3 and FGFR4. However, Apert cells had increased cell growth compared with control cells. Distinct from previous findings in osteoblast cells, gain-of-function S252W FGFR2 mutation did not upregulate the expression of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFRα), but elevated extracellular signal-regulated kinase (ERK) signaling in cells after EGF stimulation. Unexpectedly, there was little effect of the S252W mutation on odontogenic gene expression in dental pulp and EOE cells. However, after inhibition of total FGFR signaling or ERK signaling, the expression of odontogenic genes was upregulated in both dental cell types, indicating the negative effect of whole FGFR signaling on odontogenic differentiation. This study provides novel insights on FGFR signaling and a common Apert FGFR2 mutation in the regulation of odontogenic differentiation of dental mesenchymal and epithelial cells.
authors.affiliation: Institute of Oral Health Research, School of Dentistry, UAB - The University of Alabama at Birmingham, Birmingham, Ala., USA.
authors.forename: Changming
authors.initials: C
authors.lastname: Lu
authors.forename: Samuel
authors.initials: S
authors.lastname: Huguley
authors.forename: Chun
authors.initials: C
authors.lastname: Cui
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Cabaniss
authors.forename: Peter D
authors.initials: PD
authors.lastname: Waite
authors.forename: David M
authors.initials: DM
authors.lastname: Sarver
authors.forename: Olga A
authors.initials: OA
authors.lastname: Mamaeva
authors.forename: Mary
authors.initials: M
authors.lastname: MacDougall
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics*; D000469:Alkaline Phosphatase / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D003782:Dental Pulp / Q000166:cytology*; D004658:Enamel Organ / Q000166:cytology*; D066246:ErbB Receptors / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D009805:Odontogenesis / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000096:biosynthesis; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000096:biosynthesis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis; D015398:Signal Transduction; D014070:Tooth / Q000196:embryology*
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; C496371:FGFR4 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; D020796:Receptor, Platelet-Derived Growth Factor alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D000469:Alkaline Phosphatase