Novel Molecular Pathways Elicited by Mutant FGFR2 May Account for Brain Abnormalities in Apert Syndrome
Carregando...
Citações na Scopus
11
Tipo de produção
article
Data de publicação
2013
Editora
PUBLIC LIBRARY SCIENCE
Indexadores
Título da Revista
ISSN da Revista
Título do Volume
Autores
YEH, Erika
FANGANIELLO, Roberto D.
SUNAGA, Daniele Y.
ZHOU, Xueyan
HOLMES, Gregory
ROCHA, Katia M.
WANG, Yingli
JABS, Ethylin W.
Autor de Grupo de pesquisa
Editores
Coordenadores
Organizadores
Citação
PLOS ONE, v.8, n.4, article ID e60439, 7p, 2013
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.
Palavras-chave
Referências
- Agochukwu NB, 2012, CHILD NERV SYST, V28, P1447, DOI 10.1007/s00381-012-1756-2
- Aldridge K, 2010, DEV DYNAM, V239, P987, DOI 10.1002/dvdy.22218
- BASILICO C, 1992, ADV CANCER RES, V59, P115, DOI 10.1016/S0065-230X(08)60305-X
- Boilly B, 2000, CYTOKINE GROWTH F R, V11, P295, DOI 10.1016/S1359-6101(00)00014-9
- CHADI G, 1993, EXP BRAIN RES, V97, P145
- COHEN MM, 1994, J CRAN GENET DEV BIO, V14, P153
- COHEN MM, 1992, CLIN GENET, V41, P12
- COHEN MM, 1990, AM J MED GENET, V35, P36, DOI 10.1002/ajmg.1320350108
- COHEN MM, 1993, AM J MED GENET, V45, P758, DOI 10.1002/ajmg.1320450618
- Cohen MMMRE, 2000, CRANIOSYNOSTOSIS DIA
- DELEON DD, 1987, BIOL REPROD, V37, P1066, DOI 10.1095/biolreprod37.5.1066
- ECKENSTEIN F, 1991, ANN NY ACAD SCI, V638, P348, DOI 10.1111/j.1749-6632.1991.tb49045.x
- ECKENSTEIN FP, 1994, J NEUROBIOL, V25, P1467
- Emoto N, 1989, Growth Factors, V2, P21, DOI 10.3109/08977198909069078
- Fanganiello RD, 2007, MOL MED, V13, P422, DOI 10.2119/2007-00027.Fanganiello
- Hart AW, 2000, NATURE, V408, P864
- Hong FX, 2006, BIOINFORMATICS, V22, P2825, DOI 10.1093/bioinformatics/btl476
- Ibrahimi OA, 2004, HUM MOL GENET, V13, P2313, DOI 10.1093/hmg/ddh235
- Johnson D, 2011, EUR J HUM GENET, V19, P369, DOI 10.1038/ejhg.2010.235
- Cohen M M Jr, 1991, Neurosurg Clin N Am, V2, P565
- Legeai-Mallet L, 1998, J BIOL CHEM, V273, P13007, DOI 10.1074/jbc.273.21.13007
- Mangasarian K, 1997, J CELL PHYSIOL, V172, P117, DOI 10.1002/(SICI)1097-4652(199707)172:1<117::AID-JCP13>3.0.CO;2-9
- Mansukhani A, 2005, J CELL BIOL, V168, P1065, DOI 10.1083/jcb.200409182
- Moloney DM, 1996, NAT GENET, V13, P48, DOI 10.1038/ng0596-48
- NEILSON KM, 1995, J BIOL CHEM, V270, P26037
- Passos-Bueno Maria Rita, 2008, V12, P107, DOI 10.1159/0000115035
- Quintero-Rivera F, 2006, AM J MED GENET A, V140A, P1337, DOI 10.1002/ajmg.a.31277
- Raybaud C, 2007, CHILD NERV SYST, V23, P1379, DOI 10.1007/s00381-007-0474-7
- Renier D, 2000, CHILD NERV SYST, V16, P645, DOI 10.1007/s003810000320
- Saeys Y, 2007, BIOINFORMATICS, V23, P2507, DOI 10.1093/bioinformatics/btm344
- Sahni M, 1999, GENE DEV, V13, P1361, DOI 10.1101/gad.13.11.1361
- Tusher VG, 2001, P NATL ACAD SCI USA, V98, P5116, DOI 10.1073/pnas.091062498
- Vandesompele J, 2002, GENOME BIOL, P3
- Verpy E, 2011, J COMP NEUROL, V519, P194, DOI 10.1002/cne.22509
- Verpy E, 2008, NATURE, V456, P255, DOI 10.1038/nature07380
- Verpy E, 2001, NAT GENET, V29, P345, DOI 10.1038/ng726
- Wang YL, 2005, DEVELOPMENT, V132, P3537, DOI 10.1242/dev.01914
- Wettenhall JM, 2004, BIOINFORMATICS, V20, P3705, DOI 10.1093/bioinformatics/bth449
- Yacubian-Fernandes A, 2004, J NEURORADIOLOGY, V31, P116, DOI 10.1016/S0150-9861(04)96978-7
- Yeh E, STEM CELL REV
- Yu K, 2000, P NATL ACAD SCI USA, V97, P14536, DOI 10.1073/pnas.97.26.14536
- Zechel S, 2010, NEUROSCIENTIST, V16, P357, DOI 10.1177/1073858410371513