Platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal cells in culture, is likely to be an important regulatory molecule in normal vertebrate development. PDGF is highly expressed in early vertebrate embryos. PDGF has a profound effect on several embryonic cell systems in vitro, suggesting that PDGF is important in cardiovascular, skeletal muscle, and central nervous system development. One way to establish the developmental function of PDGF is to interrupt growth factor receptor signalling in vivo. In our lab, a PDGF beta receptor mutant has recently been produced that inhibits wild-type beta receptor function in a dominant manner. This mutant receptor forms a dimer with wild-type receptor upon ligand stimulation, preventing subsequent signal transduction. In this proposal, the Xenopus PDGF receptors will be cloned and the spatial and temporal distribution of these receptors in embryonic development will be examined. Next, dominant negative Xenopus PDGF receptor mutants will be produced. Mutants will be introduced into early frog embryos by microinjection of receptor encoding mRNA. The effects of PDGF receptor inhibition during embryonic development will be assessed by morphologic analysis. These studies will help clarify the role of PDGF in embryogenesis. They will also provide a method to inhibit the action of PDGF in vivo and may therefore lead to the generation of therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Physician Scientist Award (K11)
Project #
5K11HL002571-05
Application #
2210198
Study Section
Research Manpower Review Committee (MR)
Project Start
1992-04-01
Project End
1997-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Barnes-Jewish Hospital
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110
Xing, H; Kornfeld, K; Muslin, A J (1997) The protein kinase KSR interacts with 14-3-3 protein and Raf. Curr Biol 7:294-300
MacNicol, A M; Muslin, A J; Williams, L T (1993) Raf-1 kinase is essential for early Xenopus development and mediates the induction of mesoderm by FGF. Cell 73:571-83
Muslin, A J; MacNicol, A M; Williams, L T (1993) Raf-1 protein kinase is important for progesterone-induced Xenopus oocyte maturation and acts downstream of mos. Mol Cell Biol 13:4197-202
Muslin, A J; Klippel, A; Williams, L T (1993) Phosphatidylinositol 3-kinase activity is important for progesterone-induced Xenopus oocyte maturation. Mol Cell Biol 13:6661-6