Fgfr1 regulates development through the combinatorial use of signaling proteins.
Fibroblast growth factor (Fgf) signaling governs multiple processes important in development and disease. Many lines of evidence have implicated Erk1/2 signaling induced through Frs2 as the predominant effector pathway downstream from Fgf receptors (Fgfrs), but these receptors can also signal through other mechanisms. To explore the functional significance of the full range of signaling downstream from Fgfrs in mice, we engineered an allelic series of knock-in point mutations designed to disrupt Fgfr1 signaling functions individually and in combination. Analysis of each mutant indicates that Frs2 binding to Fgfr1 has the most pleiotropic functions in development but also that the receptor uses multiple proteins additively in vivo. In addition to Frs2, Crk proteins and Plcγ also contribute to Erk1/2 activation, affecting axis elongation and craniofacial and limb development and providing a biochemical mechanism for additive signaling requirements. Disruption of all known signaling functions diminished Erk1/2 and Plcγ activation but did not recapitulate the peri-implantation Fgfr1-null phenotype. This suggests that Erk1/2-independent signaling pathways are functionally important for Fgf signaling in vivo.
Department of Developmental and Regenerative Biology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
J Richard
JR
Brewer
Department of Developmental and Regenerative Biology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
Andrei
A
Molotkov
Department of Developmental and Regenerative Biology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
Pierre
P
Mazot
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Renée V
RV
Hoch
Department of Developmental and Regenerative Biology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Philippe
P
Soriano
D000483:Alleles; D000818:Animals; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D004707:Endoderm / Q000196:embryology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055879:Gene Knock-In Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D047908:Intracellular Signaling Peptides and Proteins; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1
MAPK; craniofacial development; gastrulation; preimplantation; signaling