Diverse Fgfr1 signaling pathways and endocytic trafficking regulate early mesoderm development I
The Fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Fgfr1 null embryos, embryos containing hypomorphic mutations in Fgfr1 lacking the ability to activate canonical downstream signals are still able to develop to birth, but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of Fgfr1, leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM-interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identify processes regulating early mesoderm development by mechanisms involving both canonical and non-canonical Fgfr1 pathways, including direct interaction with cell adhesion components and endocytic regulation. Overall design: To investigate changes in transcription during mesoderm development with or without canonical FGF signaling, we created mouse lines containing point mutations in key effector binding residues. We then collected tailbud tissue from E8.5 mouse embryos to use for gene expression profiling. Comparative gene expression profiling between wild-type and mutant FGFR1 tissue was used to determine changes in GO and KEGG term gene sets. We compared wild type to Fgfr1 FCPG, wild type to Fgfr1 FCSPG, and Fgfr1 FCPG to Fgfr1 FCSPG.