title: Novel molecular pathways elicited by mutant FGFR2 may account for brain abnormalities in Apert syndrome.
abstract: Apert syndrome (AS), the most severe form craniosynostosis, is characterized by premature fusion of coronal sutures. Approximately 70% of AS patients carry S252W gain-of-function mutation in FGFR2. Besides the cranial phenotype, brain dysmorphologies are present and are not seen in other FGFR2-asociated craniosynostosis, such as Crouzon syndrome (CS). Here, we hypothesized that S252W mutation leads not only to overstimulation of FGFR2 downstream pathway, but likewise induces novel pathological signaling. First, we profiled global gene expression of wild-type and S252W periosteal fibroblasts stimulated with FGF2 to activate FGFR2. The great majority (92%) of the differentially expressed genes (DEGs) were divergent between each group of cell populations and they were regulated by different transcription factors. We than compared gene expression profiles between AS and CS cell populations and did not observe correlations. Therefore, we show for the first time that S252W mutation in FGFR2 causes a unique cell response to FGF2 stimulation. Since our gene expression results suggested that novel signaling elicited by mutant FGFR2 might be associated with central nervous system (CNS) development and maintenance, we next investigated if DEGs found in AS cells were also altered in the CNS of an AS mouse model. Strikingly, we validated Strc (stereocilin) in newborn Fgfr2(S252W/+) mouse brain. Moreover, immunostaining experiments suggest a role for endothelial cells and cerebral vasculature in the establishment of characteristic CNS dysmorphologies in AS that has not been proposed by previous literature. Our approach thus led to the identification of new target genes directly or indirectly associated with FGFR2 which are contributing to the pathophysiology of AS.
authors.affiliation: Human Genome Center, Department of Genetics and Evolutive Biology, Institute of Bioscience, University of Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Erika
authors.initials: E
authors.lastname: Yeh
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Fanganiello
authors.forename: Daniele Y
authors.initials: DY
authors.lastname: Sunaga
authors.forename: Xueyan
authors.initials: X
authors.lastname: Zhou
authors.forename: Gregory
authors.initials: G
authors.lastname: Holmes
authors.forename: Katia M
authors.initials: KM
authors.lastname: Rocha
authors.forename: Nivaldo
authors.initials: N
authors.lastname: Alonso
authors.forename: Hamilton
authors.initials: H
authors.lastname: Matushita
authors.forename: Yingli
authors.initials: Y
authors.lastname: Wang
authors.forename: Ethylin W
authors.initials: EW
authors.lastname: Jabs
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C440007:Strc protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2