Development of the vertebrate embryo is dependent on a series of complex cellular interactions. In the frog, the first of these interactions is termed induction, where signals emanating from the endoderm cause other cells in the early blastula to form mesoderm. Mesoderm induction, and therefore early patterning of the embryo, may be mediated by the effects of growth factors such as members of the fibroblast growth factor(FGF) family. Recent work has shown that inhibition of FGF signaling in the early Xenopus embryo leads to deficient mesoderm formation and inhibition of mesoderm specific gene expression. This data supports the requirement for FGF dependent events in early tissue specification. However, little is known about the molecular mechanisms which regulate the FGF pathway or how cells become competent to respond to FGF. Recent data indicate that translational control of maternal mRNA modulates FGF receptor protein expression in the embryo. The overall objective of this proposal is to determine the molecular mechanism(s) which regulate the translation of the maternal mRNA for the Xenopus FGF receptor during early embryogenesis. To this end, the following specific aims are proposed: 1. Localize Xenopus FGF receptor protein and maternal mRNA transcripts during early embryogenesis. Preliminary data suggests that regional specific differential translation of receptor protein within the embryo is generated from uniformly distributed maternal mRNA. Immunocytochemical and RNA in situ hybridization analysis will be performed to map the temporal and spatial expression of protein and maternal RNA in the blastula and early gastrula embryo. 2. Determine the specific regions of 3' untranslated sequences involved in translational regulation. In the oocyte, maternal transcripts of the FGF receptor are inhibited from translation, and appear to involve RNA-protein interactions in untranslated regions. Regions of 3' untranslated sequences will be studied by deletional analysis to define specific sequences involved in this regulation. 3. Identify RNA-binding proteins involved in translational repression of Xenopus FGF receptor RNA. Studies are proposed to further characterize FGF receptor maternal mRNA binding proteins in cell-free extracts and will form the basis for cloning specific cytoplasmic RNA binding proteins. These studies will provide new insights into the molecular mechanisms controlling patterning events in the early embryo. Greater understanding of the mechanisms of normal growth and development can ultimately shed light on the pathogenesis of human congenital malformations and malignancy.
| Culp, P A; Musci, T J (1999) c-mos and cdc2 cooperate in the translational activation of fibroblast growth factor receptor-1 during Xenopus oocyte maturation. Mol Biol Cell 10:3567-81 |
| Culp, P A; Musci, T J (1998) Translational activation and cytoplasmic polyadenylation of FGF receptor-1 are independently regulated during Xenopus oocyte maturation. Dev Biol 193:63-76 |
| Robbie, E P; Peterson, M; Amaya, E et al. (1995) Temporal regulation of the Xenopus FGF receptor in development: a translation inhibitory element in the 3' untranslated region. Development 121:1775-85 |
