Novel Molecular Pathways Elicited by Mutant FGFR2 May Account for Brain Abnormalities in Apert Syndrome

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art_ALONSO_Novel_Molecular_Pathways_Elicited_by_Mutant_FGFR2_May_2013.PDF (758.9 KB)
Citações na Scopus
11
Tipo de produção
article
Data de publicação
2013
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
PUBLIC LIBRARY SCIENCE
Autores
YEH, Erika
FANGANIELLO, Roberto D.
SUNAGA, Daniele Y.
ZHOU, Xueyan
HOLMES, Gregory
ROCHA, Katia M.
WANG, Yingli
JABS, Ethylin W.
Citação
PLOS ONE, v.8, n.4, article ID e60439, 7p, 2013
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
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URI
https://observatorio.fm.usp.br/handle/OPI/1663
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MCG
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/04
Artigos e Materiais de Revistas Científicas - ODS/03