Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development.
Fibroblast growth factor receptor 1 (Fgfr1) plays pleiotropic roles during embryonic development, but the mechanisms by which this receptor signals in vivo have not previously been elucidated. Biochemical studies have implicated Fgf receptor-specific substrates (Frs2, Frs3) as the principal mediators of Fgfr1 signal transduction to the MAPK and PI3K pathways. To determine the developmental requirements for Fgfr1-Frs signaling, we generated mice (Fgfr1(Delta)Frs/DeltaFrs) in which the Frs2/3-binding site on Fgfr1 is deleted. Fgfr1(Delta)Frs/DeltaFrs embryos die during late embryogenesis, and exhibit defects in neural tube closure and in the development of the tail bud and pharyngeal arches. However, the mutant receptor is able to drive Fgfr1 functions during gastrulation and somitogenesis, and drives normal MAPK responses to Fgf. These findings indicate that Fgfr1 uses distinct signal transduction mechanisms in different developmental contexts, and that some essential functions of this receptor are mediated by Frs-independent signaling.
Hoch
Renée V
RV
Program in Developmental Biology, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Soriano
Philippe
P
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001934:Branchial Region / Q000196:embryology / Q000378:metabolism; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D020964:Embryo Loss; D047108:Embryonic Development; D005775:Gastrula / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019170:Somites / Q000378:metabolism; D013623:Tail / Q000196:embryology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C485162:Frs3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1