FGF signaling regulates development by processes beyond canonical pathways

被引:20
作者
Ray, Ayan T. [1 ]
Mazot, Pierre [1 ,2 ]
Brewer, J. Richard [1 ,3 ]
Catela, Catarina [1 ,4 ]
Dinsmore, Colin J. [1 ]
Soriano, Philippe [1 ]
机构
[1] Icahn Sch Med Mt Sinai, Dept Cell Dev & Regenerat Biol, New York, NY 10029 USA
[2] INSERM Transfert, F-75013 Paris, France
[3] Yale Univ, Dept Immunobiol, New Haven, CT 06520 USA
[4] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA
基金
美国国家卫生研究院;
关键词
FGF; craniofacial development; neural crest; ERK1/2; cell adhesion; FIBROBLAST-GROWTH-FACTOR; EPITHELIAL-MESENCHYMAL INTERACTIONS; FACTOR RECEPTOR; CELL; DISRUPTION; BIM; PHOSPHORYLATION; FAMILY; MORPHOGENESIS; PROLIFERATION;
D O I
10.1101/gad.342956.120
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
FGFs are key developmental regulators that engage a signal transduction cascade through receptor tyrosine kinases, prominently engaging ERK1/2 but also other pathways. However, it remains unknown whether all FGF activities depend on this canonical signal transduction cascade. To address this question, we generated allelic series of knock-in Fgfr1 and Fgfr2 mouse strains, carrying point mutations that disrupt binding of signaling effectors, and a kinase dead allele of Fgfr2 that broadly phenocopies the null mutant. When interrogated in cranial neural crest cells, we identified discrete functions for signaling pathways in specific craniofacial contexts, but point mutations, even when combined, failed to recapitulate the single or double null mutant phenotypes. Furthermore, the signaling mutations abrogated established FGF-induced signal transduction pathways, yet FGF functions such as cell-matrix and cell-cell adhesion remained unaffected, though these activities did require FGFR kinase activity. Our studies establish combinatorial roles of Fgfr1 and Fgfr2 in development and uncouple novel FGFR kinase-dependent cell adhesion properties from canonical intracellular signaling.
引用
收藏
页码:1735 / 1752
页数:18
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