The role of FGF signaling in neural crest development

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Montana State University - Bozeman, College of Letters & Science


The mechanisms that stimulate Neural Crest Cell (NCC) migration and cessation into discrete sympathetic ganglia (SG) and dorsal root ganglia (DRG) are incompletely understood. In this study we investigated the role of Endothelial Cells (ECs) and the shared growth factors of the nervous and vascular system: fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) in the development of the peripheral nervous system. We hypothesized that ECs impact neural crest patterning. Using live time-lapse microscopy, we found that NCCs and ECs interact extensively during neural crest migration and DRG development, including stimulating proliferation of Pax3+ neural progenitors. These studies also revealed that ECs of the intersomitic vessel perhaps act as a substrate for migrating NCCs while the perisomitic vessel acted as a boundary keeping NCCs in the forming DRG. In order to determine the role of ECs in PNS development we focally eliminated them with FGF receptor (FGFR) blocker Su5402. Su5402 focally reduced ECs and caused NCCs to remain dorsal. Given that FGFs effects could be direct or indirect on NCC, we sought to reduce FGF signaling solely in NCe. To this end we overexpressed a dominant negative FGFRl (DNFGFR1) and FGFR3 in ovo in NCCs. Our studies demonstrated that while blocking FGFR3 signaling did not impair NCC migration, NCCs expressing the DNFGFRl behaved similarly as did the Su4502 treated NCCs: they stayed dorsally at the expense of the SG and DRG and exhibited distinct morphologies. Stimulating FGFR signaling with the ligand FGF8 promoted migration in vitro and increased ventral migration of NCCs in vivo. To determine if the alterations in DNFGFRl + NCCs was due to changes in cell adhesion molecule function, we transfected NCC with DNFGFRl and gain and loss of function Ncadherin constructs. Surprisingly the fate of DNFGFR1+ NCCs was rescued by increasing expression of N-cadherin, while double transfections of DNFGFRl and DN-N-cadherin further impaired migration. While it is possible that N-cadherin and FGFRl directly interact, the exact interactions of FGFRl and N-cadherin need to be further investigated. FGFR3 was not found to function in NCC migration, but preliminary findings show it is required for TrkA+ neural differentiation.




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