The broad objective of this proposal is to obtain an understanding of the functional role played by members of the fibroblast growth factor (FGF) family of paracrine regulatory peptides during development of the peripheral and central nervous systems, and to understand how the FGF family of factors may interact with the NGF family of neurotrophic factors. Acidic and basic FGF have neurotrophic activity of a variety of neuronal populations in vitro. 5 additional members of the FGF family of growth factors have been clones but it is unclear whether they may act as neurotrophic factors. If these multiple FGF isoforms have neurotrophic functions in vivo, it is likely that they are critically important for normal development of the nervous system, and defects in their action may be important in neurodegenerative diseases. Preliminary studies demonstrate that CNS development is characterized by alternating phases by expression of FGF receptor (FGFR) and NGF receptor (NGFR) suggesting that FGF and NGF may act sequentially in neural development. The following hypotheses will be tested: 1) that FGF's are biologically relevant neurotrophic factors. 2) that neurons express several distinct FGFR isoforms capable of discriminating among various members of the FGF family. 3) that multiple FGF isoforms are expressed in the developing nervous system and that individual isoforms have specific functional roles. 4) that alternating phases of FGFR and NGFR expression during CNS development may be the result of direct regulatory mechanisms whereby FGF may induce NGFR expression during neuronal differentiation, while NGF may induce FGFR expression during later phases of neuronal maturation. Chicken will be used as the experimental animal. Molecular clones of chicken homologs of various FGF's and FGFR's will be isolated. In situ hybridization will be used to characterize the pattern of expression of these species during neural development. FGF and FGFR proteins will be expressed and specificity of various FGF isoforms for various FGFR isoforms will be determined. Functionally blocking antibodies against FGFR will be generated and the effects of these antibodies on neural development will be examined. The ability of NGF and FGF to induce expression of NGFR and FGFR will be examined on neural cultures.
